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Division of Immunology, Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The role of IL-2 in the regulation of immune responses to infectious agents in vivo remains unknown. Few studies have examined this issue, although a number of systems have been used to test the role of IL-2 in the growth and deletion of CD4 and CD8 T cells in response to model Ags or superantigens. Overall, the available data suggest that for CD4 T cells, IL-2 is not an essential growth factor in vivo but may play a role in inducing apoptosis in responding CD4 T cells (10, 19, 20, 21, 22), although the latter is not always the case (23). The role of IL-2 in CD8 T cell immune responses has also been studied, although to only a limited extent. Superantigen-induced expansion of splenic CD8 T cells was partially impaired in IL-2-/- mice (20), while peptide immunization of influenza nucleoprotein-specific F5 IL-2-/- TCR transgenic mice resulted in normal expansion of CD8 T cells (24). With regard to the role of IL-2 in CD8 T cell responses to virus infections, only the responses to lymphocytic choriomeningitis virus and vaccinia virus infections have been studied. In one case the response to both of these infections was largely IL-2 independent (25), while in two other studies, which assessed the total increase in splenic CD8 T cell number during lymphocytic choriomeningitis virus infection, a lack of endogenous IL-2 severely inhibited the expansion of CD8 T cells (26, 27). Regarding the contraction phase of antiviral T cell responses, cytokine deprivation has been proposed to be responsible for the loss of activated T cells (28, 29, 30); therefore, cell death may be attributed to the withdrawal of growth factors such as IL-2. Recent work also suggests that IL-2 is needed to maintain memory cells (31) or, conversely, is required to regulate CD8 memory T cell levels by inducing cell death (32, 33).
Thus, to date our knowledge of the in vivo requirement for IL-2 in the regulation of the different stages of CD8 T cell immune responses is equivocal. Also, this information is based primarily on analysis of splenic and lymph node (LN)3 T cells, which make up only a portion of the overall immune response (34, 35, 36). That is, following primary activation CD8 T cells migrate to many tertiary tissues such as the lung, liver, and intestinal mucosa (35, 37, 38, 39, 40, 41), and there is little information regarding the role of IL-2 in the control of cell expansion and death in these and other nonlymphoid tissues. Additionally, whether IL-2 encountered via autocrine or paracrine pathways may exert differential effects on T cell responses is unknown. Indeed, the fact that both sources of IL-2 may be relevant and that IL-2 can exert both growth-promoting and death-inducing effects has probably contributed to some of the present discrepancies in the literature. Thus, we set out to characterize the in vivo requirement for IL-2 at the different stages of a CD8 T cell response to a virus infection. The system used provided the means to distinguish between the effects of autocrine and paracrine IL-2 on lymphoid and nonlymphoid CD8 T cell responses. The results conclusively demonstrated that IL-2 was dispensable as a growth factor for antiviral CD8 T cells in secondary lymphoid tissues, but played an important role in augmenting the growth of CD8 T cells in nonlymphoid tissues. Intriguingly, autocrine IL-2 alone was also capable of limiting the overall magnitude of the response within nonlymphoid tissues.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6J, C57BL/6-IL-2-/-, and
C57BL/6-CD25-/- mice were obtained from The
Jackson Laboratory (Bar Harbor, ME). C57BL/6-Ly5.2 mice were obtained
from Charles River (Wilmington, MA) through the National Cancer
Institute. The OT-I mouse line (42) was provided by
W. R. Heath (Walter and Eliza Hall Institute, Parkville,
Australia) and F. Carbone (Monash Medical School, Prahran, Australia).
OT-I mice were mated to IL-2+/- mice. Offspring
were screened for the IL-2 mutation by PCR, and the presence of the
OT-I transgene was detected by assessing the frequency of
V
2+ V
5+
CD8+ cells in PBL.
OT-I/IL-2+/- mice were then intercrossed to
obtain OT-I/IL-2-/- animals.
OT-I/CD25-/- animals were generated in a
similar manner. OT-I-lpr/lpr mice were provided by Dr. R.
Budd (University of Vermont, Burlington, VT). For in vivo
proliferation assays mice were provided with water ad libitum
supplemented with 0.8 mg/ml 5'-bromodeoxyuridine (BrdU; Sigma-Aldrich,
St. Louis, MO) for 43 days as described by Tough and Sprent
(43).
Isolation of lymphocyte populations
Intraepithelial lymphocyte (IEL) and lamina propria (LP) cells from small intestine were isolated as previously described (44, 45). Spleens and LN were removed, and single-cell suspensions were prepared using a tissue homogenizer. The resulting preparation was filtered through Nitex nylon mesh (Tetko, Kansas City, MO), and the filtrate was centrifuged to pellet the cells. To obtain lymphocytes from livers and lungs, anesthetized mice were perfused with PBS containing 75 U/ml heparin until the tissue was cleared of blood, the organs were removed, and cells were isolated as previously described (35).
Flow cytometric analysis
Lymphocytes were resuspended in PBS/0.2% BSA/0.1%
NaN3 at a concentration of 1–10 x
106 cells/ml, followed by incubation of 100 µl
of cells at 4°C for 20 min with 100 µl of properly diluted mAb or
at room temperature for 1 h with a PE-labeled MHC class I
(H-2Kb) tetramer containing the immunodominant
epitope of the nucleoprotein of vesicular stomatitis virus (VSV)
(35). mAbs specific for the following Ags and coupled to
the indicated fluorochromes were used: V5-FITC, V2-PE, CD25-PE,
CD44-PE, CD8-PerCP, CD8-allophycocyanin, and CD4-PE (all from BD
PharMingen, San Diego, CA); CD8-(3.168)-FITC or -biotin
(46); and Ly5.1- or Ly5.2-FITC or -Cy5 (47).
Streptavidin-PE-Cy7 (Caltag Laboratories, Burlingame, CA) was used to
detect biotinylated mAb. Anti-BrdU staining was performed as described
by Tough and Sprent (43). Relative fluorescence
intensities were measured with a FACSCalibur (BD Biosciences, San Jose,
CA). Data were analyzed using WinMDI software (J. Trotter, Scripps
Clinic, La Jolla, CA).
Adoptive transfer of OT-I, OT-I-IL-2-/-, and OT-I-CD25-/- cells
For adoptive transfer, each cell type was injected i.v. into B6-Ly5.2 mice or B6-IL-2-/- mice either separately or as a mixture containing an equal number (0.5 x 106 or 1 x 106 cells) of OT-I T cells and mutant OT-I cells from LN. In some experiments the donor cells were labeled with the viable dye CFSE (0.01 mM) (Molecular Probes, Eugene, OR) before transfer. Twenty-four hours later mice were infected i.v. with 1 x 106 PFU of recombinant VSV-OVA (48), and at various time points postinfection cells were isolated for analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Results obtained from previous in vivo studies using
IL-2-deficient mice may have been confounded by the fact that these
animals become severely immunocompromised at an early age
(25). Studies using either intact
IL-2-/- or CD25-/- TCR
transgenic mice or the adoptive transfer of T cells from these mice
have also been performed. However, in these cases peptide or whole
protein was the usual immunogen, and only splenic or LN responses were
examined (21, 22, 24). Therefore, we introduced the OT-I
TCR transgenes (42) (V2 and V5) into IL-2-deficient
or IL-2R (CD25)-deficient mice for use in adoptive transfer studies
in which hosts are virus-infected and multiple tissues are examined.
OT-I T cells are CD8+ and recognize the SIINFEKL
peptide derived from chicken OVA in the context of MHC class I
H-2Kb. The presence of TCR transgenes delayed the
onset of lymphoproliferative and inflammatory bowel disease in these
mice, and all cells used for transfers were from healthy 4- to 5-wk-old
animals.
We have previously shown that transfer of small numbers of OT-I cells
into normal B6 mice followed by infection with a recombinant VSV
containing the OVA gene (VSV-OVA) results in robust expansion of OT-I
cells in lymphoid tissues as well as in intestinal LP and epithelium
(39, 40). To test the role of autocrine IL-2 in this
system, trackable OT-I (Ly5.1) or OT-I-IL-2-/-
(Ly5.1) cells were transferred separately to B6-Ly5.2 hosts, which were
then infected with VSV-OVA. Before immunization the transferred
populations were detected in equal numbers in the blood, and each
represented 
0.3% of lymphocytes (data not shown). Four days after
infection, at the peak of the primary response, OT-I and
OT-I-IL-2-/- cells had expanded equally well in
the LN and spleen (Fig. 1
A,
top and middle panels). In the intestinal LP
significant expansion also occurred, but the increase in
OT-I-IL-2-/- cells was routinely inhibited to
60% of the control values. This result suggested that autocrine
IL-2 was needed for maximal CD8 T cell expansion in the LP, but not in
secondary lymphoid tissues. To allow a direct comparison between
wild-type and mutant OT-I cells within the same recipients we
transferred equal numbers of OT-I (Ly5.1/5.2) and
OT-I-IL-2-/- (Ly5.1) cells as a mixture into
naive B6-Ly5.2 recipients. Analysis of the PBL of the recipient mice
before immunization confirmed an equal ratio of the two cell types
(data not shown). After VSV-OVA infection, both populations expanded in
roughly equal proportions in the lymphoid tissues, although there was a
small, but consistent, difference between the ratio of OT-I to
OT-I-IL-2-/- cells in spleen vs LN, with the
ratio in spleen always favoring OT-I-IL-2-/-
cells (Fig. 1A, bottom panels). In striking
contrast, in the intestinal LP, OT-I-IL-2-/-
cells outnumbered wild-type OT-I cells by 3 to 1. The fact that
OT-I-IL-2-/- cells expanded significantly
better in the presence of OT-I cells than in their absence (Fig. 1A, compare OT-I-IL-2-/- transfer
alone with transfer of the mixture in LP) suggested that paracrine IL-2
from the responding IL-2-competent OT-I cells could augment the growth
of OT-I-IL-2-/- cells in the intestinal LP. In
addition, the finding that OT-I-IL-2-/- cells
outnumbered OT-I cells suggested that measured down-regulation of the
CD8 T cell response occurred in the gut even as the size of the overall
population increased, and that autocrine IL-2 was involved in this
process.
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-chain, CD25, the observed increase in the number of
OT-I-IL-2-/- cells in the LP may have been the
result of altered CD25 levels. Naive OT-I and
OT-I-IL-2-/- cells did not express detectable
levels of CD25 before (Fig. 1
B, filled histograms) or after
transfer. However, at 56 h postimmunization CD25 was up-regulated
to similar levels on OT-I and OT-I-IL-2-/-
cells (Fig. 1B, open histograms) in the secondary lymphoid
tissues. At this time point the number of donor cells in tertiary
tissues is scant, making the analysis of CD25 on these cells difficult.
By 81 h postimmunization marked down-regulation of CD25 expression
had occurred on both donor populations in the LN, LP, and other
tertiary tissues (Fig. 1B and data not shown). At the peak
of the response (96 h) CD25 was not expressed by either cell
population (data not shown). Thus, the kinetics of expression of the
high affinity IL-2R were similar in the presence or the absence of
autocrine IL-2. At these same time points direct ex vivo IL-2
production could not be detected, but OT-I cells from all tissues
produced IL-2 following short term in vitro stimulation (data not
shown). Autocrine IL-2 regulates the size of the activated CD8 T cell population in tertiary tissue
To determine whether the dysregulated growth of
OT-I-IL-2-/- cells in the LP was a general
property of activated CD8 T cells in tertiary tissues, we analyzed the
responses in the lung, liver, and intestinal epithelium in addition to
those in LP and secondary lymphoid tissues (Fig. 2). In the absence of immunization few
naive OT-I cells are detected in intestine, lung, or liver (39, 40) (data not shown). Following VSV-OVA infection a rapid
migration and continuing expansion of CD8 T cells in nonlymphoid
tissues occurred (39, 40, 48, 49) (Fig. 2). Again, both
populations expanded in roughly equal proportions in the lymphoid
tissues. In contrast, 2.5-fold greater numbers of
OT-I-IL-2- vs wild-type OT-I cells were present
in the lung, liver, and intestine (Fig. 2), demonstrating that this
phenomenon was tertiary tissue specific.
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A), indicating that the
increased numbers of OT-I-IL-2-/- cells were
not due to increased proliferation and were probably due to decreased
apoptosis. By 88 h postinfection the cells in all tissues had
divided extensively and had lost the CFSE label.
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B). If the
Fas pathway was involved, we would expect the OT-I-lpr/lpr
cells to behave similarly to the OT-I-IL-2-/-
cells when transferred together with wild-type OT-I cells. Activation
of mixtures of OT-I and OT-I-IL-2-/- cells
again resulted in expansion skewed toward
OT-I-IL-2-/- cells in the LP and IEL (Fig. 3B, left group). In contrast,
activation of mixtures of OT-I and OT-I-lpr/lpr cells
resulted in equivalent expansion of each population in all tissues
(Fig. 3B, middle group). Transfer and activation
of mixtures of OT-I-lpr/lpr and
OT-I-IL-2-/- cells also resulted in
disproportionate growth of OT-I-IL-2-/- cells
in the intestinal mucosa, but not in the lymphoid tissues (Fig. 3B, right group). Therefore, the
increased expansion was not due to impaired Fas-mediated apoptosis. We
performed similar experiments using
OT-I-perforin-/- cells, since perforin has also
been implicated in down-modulation of CD8 T cell responses
(50, 51, 52). However, the ratio of wild-type to
OT-I-perforin-/- cells in all tissues after
infection remained 1:1 (data not shown), indicating that perforin
was not responsible for the observed effects. IL-2 has also been
suggested to limit T cell expansion via down-regulation of
intracellular Bcl-2 levels as well as the common 
-chain, which is
used by the IL-2R and other receptors for growth-promoting cytokines
such as IL-7 and IL-15 (9, 53). OT-I and
OT-I-IL-2-/- cells displayed equivalent surface
expression of the common -chain and intracellular Bcl-2 levels
before and following activation in vivo (data not shown), implying that
altered levels of these molecules were not responsible for the observed
phenomenon. Requirement for IL-2 in optimal CD8 T cell expansion in tertiary tissue
It was clear from the previous experiments that although the CD8 T
cells displayed impaired proliferation within tertiary tissues in the
absence of autocrine IL-2 (Fig. 1), their expansion was still
substantial. However, the experiments to date did not rule out the
participation of paracrine IL-2 produced by host T cells. Thus, to
determine the overall requirement for IL-2 in the antiviral OT-I
response, we transferred OT-I-IL-2-/- cells to
young B6 or IL-2-/- hosts, which were then
infected with VSV-OVA, and lymphocytes were analyzed 4 days later.
Consistent with the previous data, OT-I-IL-2-/-
cells proliferated in spleen and LP when transferred to B6 mice in
response to viral infection. However, upon transfer and infection in
IL-2-/- mice, the response was partially
inhibited in the spleen, but was inhibited to a greater extent in the
LP (Fig. 4A). This result
along with that shown in Fig. 1A indicated that CD8 T cells
in the LP were responding to both autocrine and paracrine IL-2 to
realize optimal expansion. To corroborate the role of IL-2 in responses
within tertiary tissue, we quantitated the endogenous CD8 T cell
response to VSV infection in B6 or IL-2-/- mice
using MHC class I H-2Kb tetramers. The splenic
response after infection of young IL-2-/- mice
(which had no obvious signs of lymphoproliferative or bowel disease)
was not significantly different from that of controls (Fig. 4B). However, as in the adoptive transfer studies the
response in the intestinal LP was greatly inhibited.
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). Upon transfer of OT-I and
OT-I-CD25-/- cells separately (Fig. 5, top and middle panels), the expansion of
OT-I-CD25-/- cells was equal to that of OT-I
cells in peripheral LN and was either equal to or slightly lower than
(in other experiments) that in the spleen. In the tertiary tissues,
however, there was a dramatic reduction in the number of
OT-I-CD25-/- cells. Identical results were
obtained when a mixture of OT-I and
OT-I-CD25-/- cells (Fig. 5, bottom
panel) was transferred. Here, too, the expansion of
OT-I-CD25-/- cells was similar to that of
control cells in LN, but was partially impaired in the spleen and
inhibited to a greater extent in the intestinal LP (Fig. 5) and the
liver and lung (data not shown). Notably, an increase in the number of
OT-I-CD25-/- cells in the LP and other tertiary
tissues did not occur, confirming the implication that in the mixture
of OT-I and OT-I-IL-2-/- cells (Fig. 1A), OT-I-IL-2-/- cells were
receiving paracrine IL-2, which enabled them to optimally expand. Thus,
although OT-I-CD25-/- cells in tertiary tissues
may be more resistant to apoptosis due to their inability to respond to
autocrine IL-2, their expansion was limited.
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The contraction phase of the T cell response has been suggested to
involve IL-2 (4, 7, 20, 28, 29, 30). However, the kinetics of
expression of CD25 (Fig. 1B) are in line with the hypothesis
that IL-2 plays a role during the early expansion, but not during the
contraction phase. To determine whether autocrine IL-2 was involved in
the loss of activated cells after the peak of the response, we analyzed
the ratio of OT-I to OT-I-IL-2-/- cells at 7
and 16 days postimmunization when the response was declining. The
proportions of wild-type and IL-2-deficient OT-I cells observed in the
different tissues at the peak of the response on day 4 were maintained
on days 7 and 16 during a dramatic decline in the overall number of
OT-I cells (Fig. 6A). Thus,
autocrine IL-2 was important for limiting the early response, but was
not involved in the overall contraction of the CD8 response. Similar
results were obtained when the populations were transferred separately
or when the endogenous response was measured in
IL-2-/- mice using MHC class I tetramers (data
not shown).
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55%) of OT-I and
OT-I-IL-2-/- memory cells incorporated BrdU
(Fig. 6B), indicating that the turnover of memory CD8 T
cells in secondary and tertiary lymphoid tissues was unaffected by the
absence of autocrine IL-2. Normal percentages of endogenous memory
cells were also observed in infected IL-2-/-
mice (data not shown). Thus, IL-2 was not required for antiviral memory
CD8 T cell homeostasis. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The adoptive transfer system also allowed us to track activated CD8 T cells throughout the body. We and others have recently shown that activated T cells migrate to many nonlymphoid tissues (34, 35, 36). These studies show that a substantial proportion (numerically 50% or greater) of the T cell immune response is focused in nonlymphoid tissues and that functional regulation of the response is distinct between lymphoid and nonlymphoid tissues. Our present results added another dimension to these findings by demonstrating that IL-2 was involved in the regulation of nonlymphoid, but not lymphoid, CD8 T cell responses. Thus, while responding CD8 T cells in tertiary tissues were dependent on IL-2 for optimal growth at the late stage of expansion, autocrine CD8 T cell-derived IL-2 concurrently functioned as a negative regulator of the overall expansion. These results provided an interesting in vivo example of the paradoxical roles of IL-2 in T cell responses as a growth factor and as a regulator of cell death. We also demonstrated that responding CD8 T cells provided help, in the form of paracrine IL-2, to neighboring CD8 T cells. Although the most plausible explanation for the help that was provided by OT-I cells was the provision of IL-2, another possibility was that OT-I cells modified the environment in some way and indirectly aided the proliferation of OT-I-IL-2-/- cells. The impaired proliferation of OT-I-CD25-/- cells even in the presence of OT-I cells discounted this possibility.
We hypothesized that the observed difference between wild-type OT-I cells and OT-I-IL-2-/- cells in tertiary tissues was probably due to increased proliferation, decreased apoptosis, or a combination of both during the expansion phase of the immune response. An alternative explanation was that an alteration occurred in the dynamics of lymphocyte homing as a consequence of OT-I development in the absence of IL-2 or in the absence of autocrine IL-2-mediated signaling. Although we have not discounted this possibility, it seems unlikely, because increased numbers of OT-I-IL-2-/- cells were observed only when the cells were transferred along with wild-type cells and also were observed in all tertiary tissues analyzed. In addition, OT-I-CD25-/- cells homed normally to all nonlymphoid tissues, but did not exhibit an abnormal increase in numbers at the peak of the response. The CFSE-labeling experiments demonstrated that OT-I-IL-2-/- cells divided at the same rate as wild-type OT-I cells, ruling out increased proliferation as being the contributing factor. To date we have been unable to detect apoptotic cells during the immune response in vivo, probably due to the rapid removal of dying cells by phagocytic cells. Nevertheless, the data derived from past in vitro and in vivo studies of IL-2 function support the likelihood that IL-2 in this case was inducing cell death. Because the ability to down-regulate the response was a function unique to autocrine IL-2, the question is raised of how T cells distinguish between autocrine and paracrine IL-2. The concentration of IL-2 to which the cell is exposed could be an important factor, and a cell that responds to autocrine IL-2 in addition to paracrine IL-2 might be expected to be exposed to higher cytokine concentrations. The anatomy of the tissue in which the responding CD8 T cell is located is also likely to have a significant influence, because the structure of the LN where the immune response is initiated is geared toward promotion of lymphocyte-lymphocyte interactions. In contrast, the location of lymphocyte and APC subsets in tertiary tissues such as the intestinal LP has no obvious organizational scheme. IL-2 can also be bound by the extracellular matrix (54), which may provide a platform for interaction of T cells with cytokines, but whether there are differences in the display of IL-2 in different tissues and whether matrix-bound IL-2 plays a role in immune responses are not known.
Our hypothesis, then, is that following interaction of CD8 T cells with APC in secondary lymphoid tissue (primarily in LN), initial IL-2-independent expansion occurs, followed by rapid migration of activated CD8 T cells to tertiary tissues. In the tissues the requirement for IL-2 as a growth factor gains prominence. The cells respond to autocrine and paracrine IL-2, which support continued in situ expansion. Limiting the maximum magnitude of the response during the expansion phase is probably achieved by the induction of apoptosis in a subpopulation of responding cells, and we propose that in tertiary tissues this event is controlled by autocrine IL-2. Our results also established that in the CD8 T cell response to virus infection, the contraction of the responding population was not the result of activation-induced cell death induced by IL-2 nor was it due to deprivation of IL-2. The generation and maintenance of memory cells also were not dependent on IL-2. Overall, our results suggested mechanisms by which dysregulation of immune responses outside of the lymphoid tissue could adversely affect the outcome of the response, perhaps resulting in tissue-specific autoimmunity, such as occurs in IL-2-deficient mice. This system will allow eventual dissection of the molecular basis of IL-2-mediated control of the immune response.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Leo Lefrançois, Department of Medicine, University of Connecticut Health Center, MC1319, 263 Farmington Avenue, Farmington, CT 06030-1319. E-mail address: llefranc{at}neuron.uchc.edu
3 Abbreviations used in this paper: LN, lymph node; BrdU, 5'-bromodeoxyuridine; IEL, intraepithelial lymphocyte; LP, lamina propria; VSV, vesicular stomatitis virus.
Received for publication January 24, 2002. Accepted for publication April 1, 2002.
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E. Bolesta, A. Kowalczyk, A. Wierzbicki, C. Eppolito, Y. Kaneko, M. Takiguchi, L. Stamatatos, P. A. Shrikant, and D. Kozbor Increased Level and Longevity of Protective Immune Responses Induced by DNA Vaccine Expressing the HIV-1 Env Glycoprotein when Combined with IL-21 and IL-15 Gene Delivery J. Immunol., July 1, 2006; 177(1): 177 - 191. [Abstract] [Full Text] [PDF]
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 H. Jin, D. Gong, D. Adeegbe, A. L. Bayer, C. Rolle, A. Yu, and T. R. Malek Quantitative assessment concerning the contribution of IL-2R{beta} for superantigen-mediated T cell responses in vivo Int. Immunol., April 1, 2006; 18(4): 565 - 572. [Abstract] [Full Text] [PDF]
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T. Yajima, K. Yoshihara, K. Nakazato, S. Kumabe, S. Koyasu, S. Sad, H. Shen, H. Kuwano, and Y. Yoshikai IL-15 Regulates CD8+ T Cell Contraction during Primary Infection J. Immunol., January 1, 2006; 176(1): 507 - 515. [Abstract] [Full Text] [PDF]
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 D. G. Brooks, L. Teyton, M. B. A. Oldstone, and D. B. McGavern Intrinsic Functional Dysregulation of CD4 T Cells Occurs Rapidly following Persistent Viral Infection J. Virol., August 15, 2005; 79(16): 10514 - 10527. [Abstract] [Full Text] [PDF]
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P. M. Manders, P. J. Hunter, A. I. Telaranta, J. M. Carr, J. L. Marshall, M. Carrasco, Y. Murakami, M. J. Palmowski, V. Cerundolo, S. M. Kaech, et al. Inaugural Article: BCL6b mediates the enhanced magnitude of the secondary response of memory CD8+ T lymphocytes PNAS, May 24, 2005; 102(21): 7418 - 7425. [Abstract] [Full Text] [PDF]
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P. R. Burkett, R. Koka, M. Chien, S. Chai, D. L. Boone, and A. Ma Coordinate Expression and Trans Presentation of Interleukin (IL)-15R{alpha} and IL-15 Supports Natural Killer Cell and Memory CD8+ T Cell Homeostasis J. Exp. Med., October 4, 2004; 200(7): 825 - 834. [Abstract] [Full Text] [PDF]
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R. M. Teague, R. M. Tempero, S. Thomas, K. Murali-Krishna, and B. H. Nelson Proliferation and Differentiation of CD8+ T Cells in the Absence of IL-2/15 Receptor {beta}-Chain Expression or STAT5 Activation J. Immunol., September 1, 2004; 173(5): 3131 - 3139. [Abstract] [Full Text] [PDF]
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D. K. Sojka, D. Bruniquel, R. H. Schwartz, and N. J. Singh IL-2 Secretion by CD4+ T Cells In Vivo Is Rapid, Transient, and Influenced by TCR-Specific Competition J. Immunol., May 15, 2004; 172(10): 6136 - 6143. [Abstract] [Full Text] [PDF]
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J. Kan-Mitchell, B. Bisikirska, F. Wong-Staal, K. L. Schaubert, M. Bajcz, and M. Bereta The HIV-1 HLA-A2-SLYNTVATL Is a Help-Independent CTL Epitope J. Immunol., May 1, 2004; 172(9): 5249 - 5261. [Abstract] [Full Text] [PDF]
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B. H. Nelson IL-2, Regulatory T Cells, and Tolerance J. Immunol., April 1, 2004; 172(7): 3983 - 3988. [Abstract] [Full Text] [PDF]
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P. Wong and E. G. Pamer Disparate In Vitro and In Vivo Requirements for IL-2 During Antigen-Independent CD8 T Cell Expansion J. Immunol., February 15, 2004; 172(4): 2171 - 2176. [Abstract] [Full Text] [PDF]
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W. N. D'Souza and L. Lefrancois IL-2 Is Not Required for the Initiation of CD8 T Cell Cycling but Sustains Expansion J. Immunol., December 1, 2003; 171(11): 5727 - 5735. [Abstract] [Full Text] [PDF]
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M. P. Rubinstein, A. N. Kadima, M. L. Salem, C. L. Nguyen, W. E. Gillanders, and D. J. Cole Systemic Administration of IL-15 Augments the Antigen-Specific Primary CD8+ T Cell Response Following Vaccination with Peptide-Pulsed Dendritic Cells J. Immunol., November 1, 2002; 169(9): 4928 - 4935. [Abstract] [Full Text] [PDF]
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L. E. Cheng and P. D. Greenberg Selective Delivery of Augmented IL-2 Receptor Signals to Responding CD8+ T Cells Increases the Size of the Acute Antiviral Response and of the Resulting Memory T Cell Pool J. Immunol., November 1, 2002; 169(9): 4990 - 4997. [Abstract] [Full Text] [PDF]
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