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* Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia; and
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105
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expression following stimulation with peptide, while the quality of the response was determined by the intensity of staining and the distribution of CD8+ T cells producing TNF-
and IL-2. Both the levels of expression and the prevalence of TNF-+ and IL-2+ cells reflected the likely Ag load, with clear differences being identified for populations from the alveolar space vs the lung parenchyma. Irrespective of the site or time of T cell recovery, IL-2+ cells were consistently found to be a subset of the TNF-+ population which was, in turn, contained within the IFN-+ set. The capacity to produce IL-2 may thus be considered to reflect maximum functional differentiation. The hierarchy in cytokine expression throughout the acute phase of the primary and secondary response tended to be DbPA224 > DbNP366. Both elution studies with the cognate tetramers and experiments measuring CD8
coreceptor dependence for peptide stimulation demonstrated the same DbPA224 > DbNP366 profile for TCR avidity. Overall, the quality of any virus-specific CD8+ T cell response appears variously determined by the avidity of the TCR-pMHC interaction, the duration and intensity of Ag stimulation characteristic of the particular tissue environment, and the availability of CD4+ T help. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF- production being associated with the DbPA224-specific set (12). Classically, both the clonal expansion and activation of CD8+ T cells are thought to be related to IL-2 production by the CD4+ subset (15, 16). It is certainly the case that IL-2–/– mice are severely impaired in their ability to control viral infections, probably due in large part to greatly reduced CD8+ T cell responses (17). Although the capacity to establish both optimal CD8+ T cell memory and to mount an effective secondary response is diminished in CD4+ T cell-deficient I-Ab–/– mice (1, 5, 18, 19, 20), their primary virus-specific CD8+ T cell responses are relatively normal (21), suggesting the presence of an alternative source of IL-2. Responding CD8+ T cells are known to make IL-2 (22, 23), with one study suggesting that the CD8+IL-2+ population can outnumber the CD4+IL-2+ set throughout the course of an acute infection (6).
The present experiments investigate the patterns of IL-2 production by influenza-specific CD8+ T cells, with particular emphasis on differences between the DbNP366- and DbPA224-specific responses for the CD8+ sets recovered during the effector and resolution phases of the infectious process following primary or secondary respiratory challenge with the HKx31 (H3N2) influenza A virus. These analyses indicate a qualitative superiority for the DbPA224-specific set, which correlates with the avidity of the TCR-pMHC interaction. Analysis of IFN-, TNF-, and IL-2 production by peptide-stimulated, virus-specific CD8+ T cells has also enabled us to verify and extend the observation of cytokine production hierarchies for both the DbNP366- and DbPA224-specific responses. The incorporation of multiple sample sites in the present analysis (both lymphoid and nonlymphoid) further establishes the importance of environment-related hierarchies in responsiveness. Finally, analysis of IL-2 production by CD8+ T cells in the absence of CD4+ T help indicates that there is a compensatory increase, which may be why CD4+ T cell-deficient mice are more effective than IL-2–/– mice when it comes to dealing with virus infections (17, 18, 19, 24).
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Materials and Methods |
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The majority of the female C57BL/6J (B6, H-2b) mice used in this study were bred and analyzed in the animal facility of the Department of Microbiology and Immunology at the University of Melbourne. A few were also supplied by The Jackson Laboratory (Bar Harbor ME) and were used as the I-Ab+/+ controls for the experiments performed with the female B6.I-Ab–/– mice at St. Jude Children’s Research Hospital (21). Naive mice (6–8 wk) were infected intranasally (i.n.)3 with 1 x 104 PFU of HKx31 influenza A virus, while those used to analyze the secondary response were first injected i.p. with 1.5 x 107 PFU of the A/PR8/34 (PR8) influenza A virus at least 6 wk before the HKx31 challenge. The PR8 and HKx31 viruses differ in their surface hemagglutinin (H) and neuraminidase (N) glycoproteins (H1N1 and H3N2, respectively), but share the PR8 internal components (nucleoprotein (NP), NS1, NS2, M, polymerase acid (PA), PB1, PB2) (4, 25). At the time of sampling, mice were anesthetized and exsanguinated by heart puncture, before organ perfusion with 10 U/ml heparin in PBS. Lymphocytes were obtained from the pneumonic lung (1) by bronchoalveolar lavage (BAL) and adherent cells were removed by incubating on plastic for 1 h at 37°C. Homogenized, collagenase-digested lung populations (10) from mice that had first been perfused and sampled by BAL were enriched for lymphocytes by separation on a Ficoll gradient (LSM; Cappel, MP Biomed, Irvine, CA). Single-cell preparations of spleen and mediastinal lymph nodes (MLN) were enriched for CD8+ T cells (26) using mAbs to CD4 (GK1.5) and MHC class II (TIB 120) followed by anti-rat and anti-mouse Ig-coated magnetic beads (Dynal, Oslo, Norway) and subsequent magnetic depletion.
Stimulation and intracellular cytokine staining
Enriched lymphocyte populations from the spleen, MLN, BAL, and lung were incubated for 5 h in 96-well round-bottom plates at a concentration of 0.5–2 x 106 cells/well in 200 µl of complete RPMI 1640 medium (JRH Biosciences, Lenexa, KS) containing 10% FCS, 10 U/ml recombinant human IL-2, and 0.2 µl GolgiPlug (BD Biosciences, Mountain View, CA) in the presence or absence of 1 µM of the NP366–374 or PA224–233 peptides (11, 27). The cells were then washed and surface FcRs were blocked using purified anti-mouse CD16/CD32 FcRIII/II receptor (2.4G2; BD PharMingen, San Diego, CA) before staining with anti-mouse CD8-PerCP-Cy5.5 (53–6.7; BD PharMingen) for 30 min on ice. After further washing, the cells were permeabilized by paraformaldehyde fixation, then stained with anti-IFN--FITC (XMG1.2; BD PharMingen), anti-IL-2-PE (JES6-5H4; BD PharMingen), and anti-TNF--allophycocyanin (MP6-XT22; BD PharMingen) using a BD Cytofix/Cytoperm kit (BD Biosciences) according to the manufacturer’s instructions. The data were acquired on a BD Biosiences FACScan flow cytometer and analyzed using CellQuest software (BD Immunocytometry Systems, San Jose, CA). In each assay, the percent cytokine+ for cells incubated without peptide was subtracted from the percent cytokine+ incubated with peptide to yield the final value.
In vitro culture with peptide
Pooled splenocytes (3 x 107) from five HKx31-infected naive mice were enriched for the CD8+ set, then incubated for 6 days with syngeneic irradiated splenocytes (5 x 107) prepulsed with 1 µM or 1 nM of either the NP366 or the PA224 peptide. Cell aliquots were analyzed for the expression of CD8, IFN-, TNF-, and IL-2 by stimulation for 5 h with 1 µM peptide either before, or following, in vitro culture.
Measurement of TCR avidity by tetramer dissociation
An established protocol (28) was used to measure TCR avidity by tetramer elution. Enriched lymphocyte populations from the spleen, MLN, BAL, and lung were stained with the DbNP366-PE or DbPA224-PE tetramers (11, 13) for 1 h at room temperature, washed, and incubated at 37°C in medium containing anti-H-2Db (50 µg/ml; BD PharMingen) to prevent tetramer rebinding. Cell aliquots were removed at different times into cold 1% BSA/0.02% NaN2, washed twice, and stained with anti-CD8-FITC (BD PharMingen) for 30 min on ice. After further washing, the cells were resuspended in 1% BSA/0.02% NaN2 and analyzed for residual tetramer staining using a FACScan (BD Biosciences).
Measurement of CD8 coreceptor dependence
Enriched lymphocyte populations from the spleen and BAL of infected mice were precultured in the presence of 10 µg/ml 53.5-8 anti-CD8 Ab (29). Cells were then analyzed for the expression of CD8 and IFN- as described after stimulation for 5 h with 1 µM peptide in the presence of 5 µg/ml anti-CD8 Ab.
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Results |
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Earlier experiments established that the frequency ofCD8+IFN-+ cells induced by peptide stimulation is broadly equivalent to the value determined by staining freshly isolated cell populations with the DbNP366 and DbPA224 tetramers (11, 12, 13). As a consequence, kinetic analysis of the numbers of CD8+IFN-+ cells in this study (Fig. 1) showed profiles comparable to those found previously with the tetramers. Interestingly, the cell numbers for the BAL and lung tended to be fairly similar (Fig. 1, C, D, G, and H). The cells obtained by BAL will either be in the alveolar space or readily detached from the respiratory epithelium by the infusion of saline via the trachea. The "lung" set is obtained (subsequent to BAL) by enzymatic digestion of the perfused organ.
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The IFN- >TNF- >IL-2 hierarchy
Previous experiments established a distinct hierarchy in profiles of IFN- and TNF- production when BAL or spleen CD8+ T cells obtained within 21 days of virus challenge were stimulated in vitro with peptide (12). In accord with previous results, nearly all T cells producing TNF- were also positive for IFN-, although the reverse was not true (Fig. 2, A and C). Similar subsetting is observed when this analysis is extended to IL-2, with the vast majority of IL-2+ cells isolated from both the responding lymphoid tissue and the site of virus-induced pathology in the respiratory tract also producing IFN- and TNF- (Fig. 2, B and D, and data not shown). Furthermore, the results shown in Fig. 3 demonstrate quite clearly that the IL-2+ subset varies independently of the TNF-+ population across the various time points. This suggests that the acquisition of the IL-2 phenotype by the TNF-+ population may reflect a distinct cellular function rather than serving solely as a phenotypic marker of differentiation.
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The numbers of influenza-specific CD8+ T cells retrieved from the BAL and lung samples were found to be broadly similar following secondary challenge, although the BAL counts were slightly decreased relative to the lung in the primary response (Fig. 1, C, D, G, and H). Interestingly, early in the infectious process the influenza-specific BAL population contained significantly more TNF-+ cells (Fig. 3, C and D days 8 and 10; K and L, day 6) and TNF-+IL-2+ cells (Fig. 3, G and H days 8 and 10; O and P, days 6 and 8) when compared with cells in the lung set. However, this difference was either not maintained or reversed later in the response (Fig. 3, C, G, D, H, K, O, L. and P, d22, d21 and d59).
The cytokine expression profile for a particular CD8+ T cell population is determined both by the relative numbers of epitope-specific CD8+ T cells that can be induced to produce the protein in question (Figs. 1–3) and by the amount that is actually made, reflected by mean fluorescence intensity (MFI) of staining. The MFI patterns for IFN-, TNF-, and IL-2 were found to be largely similar in the primary and secondary responses, hence this analysis is shown only for CD8+ T cells recovered at the peak of the secondary response (day 8, Fig. 4, A, C, and E) and at the stage (day 21, Fig. 4, B, D, and F) where viral clearance is complete (14) and there has been some resolution in epitope-specific CD8+ T cell numbers. Analysis of the MFI values for IFN-, TNF-, and IL-2 staining on day 8 following secondary challenge revealed a clear BAL > lung hierarchy for both the DbNP366 and DbPA224 epitopes (Fig. 4, A, C, and E). The relationship was maintained for TNF- at day 21 (Fig. 4D), but the MFI profile for IFN- showed a reversal in this hierarchy (Fig. 4B) while no difference was found for the IL-2 MFI between lung and BAL at day 21 (Fig. 4F). Thus, it appears that the early superiority of the BAL vs the lung response, as measured by the proportion of specific cells producing several cytokines, is supported by the MFI data which shows that these multiple cytokine producers also make larger amounts of protein.
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The PA224 > NP366 cytokine hierarchy and correlation with TCR-epitope avidity
The present experiments (Figs. 3, A–D and I–L, and 4, A–D) reinforce the perception of a clear PA224 > NP366 hierarchy in the prevalence and quality of Ag-specific cells producing both IFN- and TNF- (12) and extend this generalization to the IL-2+IFN-+ sets (Fig. 3, E–H and M–P). Given that the DbPA224-specific cytokine response appears to be qualitatively superior to the DbNP366 response, we questioned whether this difference could be correlated with TCR-DbNP366 and TCR-DbPA224 binding avidities for CD8+ T cells recovered from the spleen, MLN, lung, and BAL. The avidity of TCR binding was first measured for CD8+ T cells from day 8 of the secondary response by determining the elution characteristic of bound tetramer (Fig. 5A). The DbPA224 tetramer was found to dissociate more slowly than the DbNP366 tetramer over a 60-min interval, suggesting that the former is the higher avidity response. To corroborate this finding we used another measure of TCR avidity, CD8 coreceptor dependence, which is based on the observation that low-avidity cells require CD8 engagement for stimulation, while high-avidity cells appear relatively CD8 independent (29, 31, 32, 33, 34). Peptide stimulation of influenza-specific CD8+ T cells in the presence or absence of CD8 Ab blockade revealed that a significantly larger percentage of the PA224-specific, compared with the NP366-specific, response is comprised of high-avidity CD8+ T cells (Fig. 5B).
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+IFN-+IL-2+ cells was maintained across tissues, with comparable patterns being found for the spleen, MLN, lung, and BAL populations (Fig. 5A). In addition, longitudinal analysis of spleen populations from secondarily challenged mice established that the profiles remain constant from the acute phase through to persistent memory (Figs. 3M and 6).
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The analysis so far indicates that freshly isolated CD8+ T cells produce cytokines in the order IFN- > TNF- > IL-2 (Figs. 2 and 3) following short-term peptide stimulation, with the relative prevalence of double (IFN-+TNF-+)- or triple-positive cells (IFN-+TNF-+IL-2+) reflecting the avidity of the interactions between the DbNP366 and DbPA224 epitopes/tetramers and their complementary, polyclonal TCR populations (Figs. 5 and 6). Analysis with other experimental systems has shown that high-avidity CD8+ T cells undergo apoptosis more readily than low-avidity populations following prolonged, in vitro exposure to high-dose peptide (32). With this in mind, splenocytes from acutely infected mice were cultured for 6 days in the presence of high (1 µM) or low (1 nM) concentrations of the NP366 or PA224 peptides (Fig. 7). After culture for 6 days with a relatively low (1 nM) dose of the cognate peptide, we found a reduction in the percentage of IL-2+ cells within the IFN-+ DbPA224-specific (but not the IFN-+ DbNP366-specific) population (Fig. 7, A, B, E, and F). This effect was accentuated following culture with the high (1 µM) peptide dose, with the IL-2+ subset being lost completely from the IFN-+ DbPA224-specific set but still detectable at reduced prevalence in the IFN-+ DbNP366-specific T cells (Fig. 7, I and J). Evidence of such extensive Ag-induced editing was not observed for the TNF--producing cells (Fig. 7, G, H, K, and L), although a reduction in the percentage of TNF-+DbPA224+ at the high peptide dose could reflect the deletion of the IL-2+ subset. Thus, prolonged, excess stimulation of the high-affinity DbPA224-specific T cells appears to result in selective deletion of the IL-2-producing set.
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and IL-2 expression is reversed following long-term in vitro stimulation with peptide (Fig. 7, E–L) suggests that this intensity and duration of T cell stimulation is not generally achieved in the in vivo situation. However, the differences for the short (5 h)- and long (6 days)-term activation profiles (Fig. 7) seem to suggest that the patterns of T cell survival in different anatomical sites may be influenced by Ag dose-related apoptotic editing. Cytokine responses in the absence of the CD4+ subset
The study so far has demonstrated that IL-2 production by virus-specific CD8+ T cells is tightly regulated, with only a small proportion of relatively highly differentiated cells capable of producing IL-2. To date, CD4+ T cells have largely been considered the crucial source of IL-2 during virus infection, with the role of CD8+ T cell-derived IL-2 remaining relatively unclear. In this study, we have investigated whether CD8+ T cells exhibit differential IL-2 production in the presence or absence of CD4+ T cells. This will provide some insight into whether CD8+ T cells have the capacity to contribute to the well-established IL-2 requirement imposed during an antiviral immune response. The prevalence of cytokine-producing CD8+ T cells in CD4+ T cell-deficient I-Ab–/– mice, assayed on day 10 after primary infection with the HKx31 virus followed the characteristic IFN- > TNF- > IL-2 and DbPA224 > DbNP366 hierarchies (Fig. 8). Interestingly, the numbers of influenza-specific cells (measured by IFN- production) were significantly higher in the spleen (but not the BAL) of the I-Ab–/–mice vs the I-Ab+/+ controls (Fig. 8, A and D). The same relationship was seen for the IL-2+IFN-+ sets (Fig. 8, C and F), although this differential was not seen for the percentage of TNF-+ populations (Fig. 8, B and E). These patterns were further reinforced by the fact that the IL-2 MFI profiles showed a small, yet significant, difference for CD8+ T cells recovered from the spleens and BAL of I-Ab–/– and I-Ab+/+ mice (Fig. 8, H and J), while no difference was found for the TNF- MFI values (Fig. 8, G and I). Thus, splenic CD8+ T cells appear to compensate for the absence of CD4+ T help by increasing the frequency and the amount of IL-2 production. This was less apparent for the BAL of I-Ab–/–mice, where the possibility of any direct or indirect interaction between CD4+ and CD8+ T cells is likely to be minimal (Fig. 8F).
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Discussion |
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and IL-2 expression measured by MFI is also seen for the percentage of IFN-+TNF-+ and percentage of IFN-+TNF-+IL-2+ in the initial and/or acute phases of both primary and secondary responses. The fact that the BAL and lung populations behave differently presumably reflects the distribution of antigenic epitopes in the infected respiratory tract. The CD8+ T cells that are recovered by BAL are likely to interact with the luminal surface of the virus-infected alveolar epithelium while the lymphocytes in the lung parenchyma may have less exposure to high levels of Ag. With the lung population, we made no attempt to discriminate between cells that might be in the bronchus-associated lymphoid tissue (BALT) vs the somatic tissue. The BALT component is minimal in the primary response of naive, specific pathogen-free B6 mice, but may be more significant following secondary challenge (35).
This study establishes clear, reproducible, and sustained hierarchies in cytokine expression profiles for influenza virus-specific CD8+ T cells. To produce TNF-, cells must also make IFN-, while IL-2 production requires that the molecular pathways for both IFN- and TNF- synthesis are also established. Hierarchical organization of cytokine responses has been described previously (IFN- > TNF-, IFN- > IL-2) in virus-specific T cell populations (6, 12, 36). As in the present study, IFN- > IL-2 patterns have been observed following in vitro stimulation of lymphocytic choriomeningitis virus-specific CD8+ T cells (6) and clonal CD4+ T cell populations (36). Furthermore, lymphocytic choriomeningitis virus-specific CD4+ T cells producing both IFN- and IL-2 showed greater TCR down-modulation than those producing IFN- alone, consistent with a higher activation state (6). Additional support for the notion that IL-2 production requires enhanced TCR signal strength comes from a study where it was observed that production of IL-2 by CD4+ T cells required long-term, stable interactions between the T cells and dendritic cells (37).
The apparent requirement for increased TCR-determined signal strength to achieve IL-2 production would explain the greater prevalence of the IL-2+ set in the BAL population recovered during the acute, Ag-driven phase of the host response. The relatively early loss of IL-2+ cells from the BAL population, along with the selective deletion of IL-2+ cells specific for DbPA224 following in vitro stimulation with high-dose peptide, also suggests that the IL-2 producers are more sensitive to high Ag load. Thus, cytokine expression profiles may provide a measure of the differentiation state of CD8+ T cells, with the most differentiated IFN-+TNF-+IL-2+ population being more sensitive to Ag-driven apoptosis.
Cytokine profiles have also been shown to vary as a function of division number (38, 39), with IL-2 expression being characteristic of the early rounds of cycling in a way that is apparently independent of lymphocyte replication. However, if we assume that signal strength is a key factor in the production of IL-2, then it is possible that the use of TCR-transgenic T cells or stimulation with anti-CD3
in these studies (38, 39) may have provided an abnormally strong signal for the induction of "early" IL-2 production. An alternative proposal is that there may be differential loss of the IL-2– population. The clonal progeny of the early dividing IL-2+ cells would then become increasingly dominant in the evolving response and make an asymmetric contribution to the establishment of memory. Although our understanding of differential proliferation and survival patterns for dividing CD8+ T cell populations in vivo is rudimentary, the profile of increased IL-2 production in the CD8+ T cells recovered from the CD4+ T cell-deficient I-Ab–/– mice suggests that IL-2 is indeed important for these processes.
The Db PA224 > DbNP366 hierarchy for IL-2 expression clearly holds for all T cells, irrespective of anatomical site. This is likely to reflect the greater avidity of the TCR-DbPA224 interaction, shown here by tetramer elution and CD8 dependence to be comparable for T cells isolated from both the lymphoid tissue and the infected lung. Furthermore, selective loss of the DbPA224-specific (compared with the DbNP366-specific) IL-2 producers following prolonged in vitro stimulation with peptide can be considered a consequence of greater apoptotic editing associated with the higher avidity TCR-epitope interaction (32, 40).
Despite observing TCR avidity differences between the DbNP366- and DbPA224-specific CD8+ T cell populations using tetramer dissociation and CD8 blocking techniques, we were unable to detect any change in the threshold of responsiveness, or "functional avidity" (29), as determined by analysis of cytokine production at diminishing peptide doses (data not shown). Thus, an apparent discrepancy exists between the TCR-pMHC avidity data and the threshold of T cell activation for the DbNP366- and DbPA224-specific CD8+ T cells. We propose that, although the inherent avidity of the DbNP366-specific TCR-pMHC interaction may be lower than that for the DbPA224-specific set, compensatory mechanisms, such as localization of signal transduction components to the TCR-CD3 complex (29) and organization of TCR and/or accessory molecules within lipid rafts (41, 42), may lead to the threshold of responsiveness for the DbNP366- and DbPA224-specific T cell populations being essentially comparable. Indeed, the greater dependence of the DbNP366-specific population on CD8 to achieve stimulation, as demonstrated in this study, suggests that localization of CD8 to the synapse may well be one such mechanism employed by the NP366-specific population. If this is true, functional avidity (29) must be considered a property of the totality of interactions comprising the immune "synapse" rather than a measure of differential affinities determined by the individual, clonotypic TCRs.
In conclusion, it seems that these cytokine response profiles for virus-specific CD8+ T cells reflect the operation of several independent hierarchies. First, the magnitude of Ag experience, as determined by anatomical location, establishes a characteristic spectrum of cytokine production following the standard 5-h in vitro stimulation with peptide. Second, differential patterns of cytokine expression are associated with the relative avidities of the TCR-DbNP366 and TCR-DbPA224 interactions. These remain constant for T cells that are localized to the spleen, the regional lymph node, the lung parenchyma, or the lung epithelium/alveolar space. Finally, the hierarchical nature of cytokine production (IFN- > TNF- > IL-2), combined with the unique propensity of the IL-2+ population to undergo apoptosis under conditions of high Ag dose, suggest that the IL-2+ population represents the most differentiated CD8+ T cell phenotype, both in the acute response and in long-term memory.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint request to Dr. Nicole La Gruta, Department of Microbiology and Immunology, University of Melbourne, Vic 3010, Australia. E-mail address: nllg{at}unimelb.edu.au
3 Abbreviations used in this paper: i.n., intranasal; NP366, peptide spanning residues 366–374 of influenza A nucleoprotein; PA224, peptide spanning residues 224–233 of influenza A acid polymerase protein; MLN, mediastinal lymph node; H, hemagglutinin; N, neuraminidase; BAL, bronchoalveolar lavage; BALT, bronchus-associated lymphoid tissue; MFI, mean fluorescence intensity.
Received for publication September 19, 2003. Accepted for publication February 13, 2004.
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E. B. Day, W. Zeng, P. C. Doherty, D. C. Jackson, K. Kedzierska, and S. J. Turner The Context of Epitope Presentation Can Influence Functional Quality of Recalled Influenza A Virus-Specific Memory CD8+ T Cells J. Immunol., August 15, 2007; 179(4): 2187 - 2194. [Abstract] [Full Text] [PDF]
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M. R. Jenkins, K. Kedzierska, P. C. Doherty, and S. J. Turner Heterogeneity of Effector Phenotype for Acute Phase and Memory Influenza A Virus-Specific CTL J. Immunol., July 1, 2007; 179(1): 64 - 70. [Abstract] [Full Text] [PDF]
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S. S. Cush, K. M. Anderson, D. H. Ravneberg, J. L. Weslow-Schmidt, and E. Flano Memory Generation and Maintenance of CD8+ T Cell Function during Viral Persistence J. Immunol., July 1, 2007; 179(1): 141 - 153. [Abstract] [Full Text] [PDF]
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S. J. Turner, E. Olivas, A. Gutierrez, G. Diaz, and P. C. Doherty Disregulated Influenza A Virus-Specific CD8+ T Cell Homeostasis in the Absence of IFN-{gamma} Signaling J. Immunol., June 15, 2007; 178(12): 7616 - 7622. [Abstract] [Full Text] [PDF]
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K. Kedzierska, J. Stambas, M. R. Jenkins, R. Keating, S. J. Turner, and P. C. Doherty Location rather than CD62L phenotype is critical in the early establishment of influenza-specific CD8+ T cell memory PNAS, June 5, 2007; 104(23): 9782 - 9787. [Abstract] [Full Text] [PDF]
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U. Malhotra, F. Li, J. Nolin, M. Allison, H. Zhao, J. I. Mullins, S. Self, and M. J. McElrath Enhanced Detection of Human Immunodeficiency Virus Type 1 (HIV-1) Nef-Specific T Cells Recognizing Multiple Variants in Early HIV-1 Infection J. Virol., May 15, 2007; 81(10): 5225 - 5237. [Abstract] [Full Text] [PDF]
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R. Keating, W. Yue, J. A. Rutigliano, J. So, E. Olivas, P. G. Thomas, and P. C. Doherty Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill J. Immunol., March 1, 2007; 178(5): 2737 - 2745. [Abstract] [Full Text] [PDF]
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C. Ranasinghe, S. J. Turner, C. McArthur, D. B. Sutherland, J.-H. Kim, P. C. Doherty, and I. A. Ramshaw Mucosal HIV-1 Pox Virus Prime-Boost Immunization Induces High-Avidity CD8+ T Cells with Regime-Dependent Cytokine/Granzyme B Profiles J. Immunol., February 15, 2007; 178(4): 2370 - 2379. [Abstract] [Full Text] [PDF]
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J. Stambas, P. C. Doherty, and S. J. Turner An In Vivo Cytotoxicity Threshold for Influenza A Virus-Specific Effector and Memory CD8+ T Cells J. Immunol., February 1, 2007; 178(3): 1285 - 1292. [Abstract] [Full Text] [PDF]
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D. M. Lindell, M. N. Ballinger, R. A. McDonald, G. B. Toews, and G. B. Huffnagle Immunologic Homeostasis during Infection: Coexistence of Strong Pulmonary Cell-Mediated Immunity to Secondary Cryptococcus neoformans Infection While the Primary Infection Still Persists at Low Levels in the Lungs J. Immunol., October 1, 2006; 177(7): 4652 - 4661. [Abstract] [Full Text] [PDF]
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M. R. Jenkins, R. Webby, P. C. Doherty, and S. J. Turner Addition of a Prominent Epitope Affects Influenza A Virus-Specific CD8+ T Cell Immunodominance Hierarchies When Antigen Is Limiting. J. Immunol., September 1, 2006; 177(5): 2917 - 2925. [Abstract] [Full Text] [PDF]
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D. C. Tscharke, W.-P. Woo, I. G. Sakala, J. Sidney, A. Sette, D. J. Moss, J. R. Bennink, G. Karupiah, and J. W. Yewdell Poxvirus CD8+ T-Cell Determinants and Cross-Reactivity in BALB/c Mice. J. Virol., July 1, 2006; 80(13): 6318 - 6323. [Abstract] [Full Text] [PDF]
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K. Kedzierska, V. Venturi, K. Field, M. P. Davenport, S. J. Turner, and P. C. Doherty Early establishment of diverse T cell receptor profiles for influenza-specific CD8+CD62Lhi memory T cells PNAS, June 13, 2006; 103(24): 9184 - 9189. [Abstract] [Full Text] [PDF]
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A. A. Divekar, D. M. W. Zaiss, F. E.-H. Lee, D. Liu, D. J. Topham, A. J. A. M. Sijts, and T. R. Mosmann Protein Vaccines Induce Uncommitted IL-2-Secreting Human and Mouse CD4 T Cells, Whereas Infections Induce More IFN-{gamma}-Secreting Cells J. Immunol., February 1, 2006; 176(3): 1465 - 1473. [Abstract] [Full Text] [PDF]
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M. M. Mangada and A. L. Rothman Altered Cytokine Responses of Dengue-Specific CD4+ T Cells to Heterologous Serotypes J. Immunol., August 15, 2005; 175(4): 2676 - 2683. [Abstract] [Full Text] [PDF]
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K. Kedzierska, N. L. La Gruta, M. P. Davenport, S. J. Turner, and P. C. Doherty Contribution of T cell receptor affinity to overall avidity for virus-specific CD8+ T cell responses PNAS, August 9, 2005; 102(32): 11432 - 11437. [Abstract] [Full Text] [PDF]
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M. M. Freeman and H. K. Ziegler Simultaneous Th1-Type Cytokine Expression Is a Signature of Peritoneal CD4+ Lymphocytes Responding to Infection with Listeria monocytogenes J. Immunol., July 1, 2005; 175(1): 394 - 403. [Abstract] [Full Text] [PDF]
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C. C. Kemball, E. D. H. Lee, V. Vezys, T. C. Pearson, C. P. Larsen, and A. E. Lukacher Late Priming and Variability of Epitope-Specific CD8+ T Cell Responses during a Persistent Virus Infection J. Immunol., June 15, 2005; 174(12): 7950 - 7960. [Abstract] [Full Text] [PDF]
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E. C. Morris, A. Tsallios, G. M. Bendle, S.-a. Xue, and H. J. Stauss A critical role of T cell antigen receptor-transduced MHC class I-restricted helper T cells in tumor protection PNAS, May 31, 2005; 102(22): 7934 - 7939. [Abstract] [Full Text] [PDF]
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D. R. Marshall, E. Olivas, S. Andreansky, N. L. La Gruta, G. A. Neale, A. Gutierrez, D. G. Wichlan, S. Wingo, C. Cheng, P. C. Doherty, et al. Effector CD8+ T cells recovered from an influenza pneumonia differentiate to a state of focused gene expression PNAS, April 26, 2005; 102(17): 6074 - 6079. [Abstract] [Full Text] [PDF]
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S. S. Andreansky, J. Stambas, P. G. Thomas, W. Xie, R. J. Webby, and P. C. Doherty Consequences of Immunodominant Epitope Deletion for Minor Influenza Virus-Specific CD8+-T-Cell Responses J. Virol., April 1, 2005; 79(7): 4329 - 4339. [Abstract] [Full Text] [PDF]
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S. Sabbaj, M. K. Ghosh, B. H. Edwards, R. Leeth, W. D. Decker, P. A. Goepfert, and G. M. Aldrovandi Breast Milk-Derived Antigen-Specific CD8+ T Cells: An Extralymphoid Effector Memory Cell Population in Humans J. Immunol., March 1, 2005; 174(5): 2951 - 2956. [Abstract] [Full Text] [PDF]
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S. R. Crowe, S. C. Miller, R. M. Shenyo, and D. L. Woodland Vaccination with an Acidic Polymerase Epitope of Influenza Virus Elicits a Potent Antiviral T Cell Response but Delayed Clearance of an Influenza Virus Challenge J. Immunol., January 15, 2005; 174(2): 696 - 701. [Abstract] [Full Text] [PDF]
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) or PA224 (
) peptide, and analyzed for expression of CD8
, p < 0.05).
PR8 challenge (see legend to Fig. 1
0.01; **, p 
