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* Department of Immunology, University of Toronto, Toronto, Canada; and
Immunology Research Division, Department of Pathology, Brigham and Women’s Hospital and Department of Pathology, Harvard Medical School, Boston, MA 02115
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In general, OX40 has more prominent effects on CD4 T cells (8) and functions to sustain CD4 T cell survival subsequent to TCR/CD28 signaling (3, 9, 10, 11, 12). Mice lacking OX40 or its ligand show defects in CD4 proliferative responses with little or no effect on CD8 T cells (13, 14, 15, 16). Similarly, mice engineered to constitutively express OX40L show expansion of CD4, but not CD8 T cells (17, 18). Conversely, agonistic Abs against 4-1BB show preferential effects on survival or expansion of CD8 T cells (19, 20, 21, 22), and mice lacking 4-1BB or its ligand show defects in recall CD8 T cell responses (23, 24, 25, 26), with no detectable effects on CD4 T cell responses to lymphocytic choriomeningitis virus or influenza virus (25, 27).
Despite the extensive literature suggesting a predominant role for OX40 on CD4 T cells and for 4-1BB on CD8 T cells, there are exceptions to this segregation of OX40 and 4-1BB function. In graft-vs-host disease models, 4-1BB/4-1BBL can play an equivalent role in MHC-I- or MHC-II-restricted disease (28), although the same is not true for OX40 (29). Furthermore, 4-1BB is required for herpes simplex 1-mediated keratinitis (30), a disease that has been attributed to the Th1 response. In adoptive transfer models, using OVA-specific TCR transgenic T cells, both OX40 and 4-1BB costimulatory pathways can influence CD4 and CD8 responses (6, 31, 32, 33). Thus, OX40 and 4-1BB can clearly influence both T cell subsets, at least in some models.
OX40- and 4-1BB-induced signals are each dependent on TNFR-associated factor 2 (34, 35, 36) and contribute to T cell survival by up-regulation of prosurvival members of the Bcl-2 family (10, 37). The possibility of OX40 and 4-1BB expression on both CD4 and CD8 T cells, their similarity in downstream signaling pathways, and their similar function in maintenance of T cell survival suggest that there could be some redundancy in their function in vivo. This possibility is further raised by the finding that blockade of the 4-1BB costimulatory pathway was found to have greater effects on primary CD8 T cell responses than 4-1BBL deficiency (31, 38), raising the possibility of compensatory effects in gene-targeted mice. To evaluate possible redundancy or cooperation between the 4-1BB and OX40 costimulatory pathways, we generated mice lacking both OX40L and 4-1BBL and evaluated the mice for responses to superantigen, influenza virus, as well as to protein Ags in an adoptive transfer model. The results suggest that OX40 and 4-1BB are expressed on different T cells or at different times in vivo, and that they act independently and noncooperatively to promote robust CD4 and CD8 recall responses, respectively.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 mice were obtained from Charles River Laboratories (St. Constant, Quebec, Canada). The 4-1BBL–/– mice (23) backcrossed onto the C57BL/6 background (n = 9) were originally obtained from J. Peschon (Amgen, Seattle, WA). OX40L–/– mice (13) (backcrossed onto the C57BL/6 background, n = 8) were crossed with the 4-1BBL–/– mice to generate the double knockout (DKO)4 mice. Genotyping of 4-1BBL locus used the primers 5'-CAC TGA CCG ACC GTG GTA ATG-3', 5'-GAC ATA GCG TTG GCT ACC CGT G-3', and 5'-AGC CCG GTA TCT CTG AGG AG-3'; and of OX40L locus, the primers 5'-AAA CTA TGG AGG TGC AGA-3', 5'-CAG AAG CAA TGT GTC TTG-3', 5'-ATT GAA CAA GAT GGA TTG CAC-3', and 5'-CGT CCA GAT CAT CCT GAT C-3'. OT-I mice (39) were provided by P. Ohashi (Toronto, Ontario, Canada), and OT-II mice (40) were provided by C. Surh (La Jolla, CA). Both transgenic mice express a V
2+ and V
5.1+ TCR and can be detected in a similar manner. For some experiments, OT-I and OT-II mice were crossed with Thy-1.1 congenic C57BL/6 mice to use as a marker for transferred T cells. Mice were maintained in the University of Toronto animal facilities, and all procedures were approved by the Animal Care Committee, following the guidelines of the Canadian Council on Animal Care.
Adoptive transfer
T cells were purified by negative selection using T Cell Immunocolumns (Cedarlane Laboratories, Hornby, Ontario, Canada) from the spleen and lymph node of either OT-I or OT-II mice. Purified T cells containing 2.5 x 106 CD8+ TCR V2+V5.1+ (OT-I) or CD4+ TCR V2+V5.1+ (OT-II) were injected i.v. into the tail vein of recipient mice. One day later, mice were injected s.c. with 2 mg of OVA (Sigma-Aldrich, St. Louis, MO) and 50 µg of LPS (Sigma-Aldrich). Mice were sacrificed at the times indicated in the figure legends.
Influenza infection
Mice were infected i.p. with 200 hemagglutinating units (HAU) of influenza A HKx31 (H3N2) and sacrificed 7 days (peak of primary response) or 21 days later. Some mice were infected i.p. a second time at day 21 with 200 HAU of a serologically distinct A/PR8/34 (H1N1) strain. The use of the second strain avoids the immunodominant neutralizing Ab response to hemagglutinin and neuraminidase proteins, which would otherwise limit reinfection and limit the secondary CTL response. Mice were sacrificed and spleen cells were harvested and evaluated for responses to the immunodominant CD8 epitope in C57BL/6 mice, nuclear protein (NP) 366–764 (41), using Db/NP366–374 tetramers (42). To enumerate influenza-specific CD8 T effector function, splenocytes were restimulated with NP366–374 peptide and analyzed by intracellular cytokine staining for IFN-
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Abs, tetramers, and flow cytometry
Anti-CD4 (GK1.5) and anti-CD8 (53.6.72) Abs were purified from hybridoma supernatants using protein G-Sepharose and biotinylated using N-hydroxysuccinimidyl-D-biotin. Biotinylated anti-TCR V5.1,5.2 (MR9-4), anti-CD134 (OX-86), FITC anti-TCR V5.1,5.2 (MR9-4), PE anti-TCR (V2 B20.1), and allophycocyanin anti-IFN- (XMG1.2) were purchased from BD Pharmingen (San Diego, CA). Biotinylated and PE anti-CD137 (17B5) and allophycocyanin streptavidin were obtained from eBioscience (San Diego, CA). Allophycocyanin-labeled tetramers containing murine class I MHC H-2Db, 2-microglobulin, and influenza nucleoprotein peptide, NP366–374, were synthesized by National Institute of Allergy and Infectious Disease MHC Tetramer Core Facility (Atlanta, GA). Cells were isolated from spleen and resuspended in staining buffer (PBS/3% FCS/0.2% azide) and 2 µg of anti-FcR (2.4G4) Ab for 10 min. Primary biotinylated Abs were added for 20 min, after which cells were washed twice with staining buffer. Cells were incubated for an additional 20 min with allophycocyanin streptavidin and the fluorescently labeled Ab and/or tetramers. Cells were washed two more times and analyzed using a FACSCalibur and CellQuest software (BD Biosciences, Mountain View, CA). For intracellular IFN- analysis, splenocytes were stimulated with 1 µM NP366–374 peptide in the presence of GolgiStop (BD Pharmingen) and stained using BD Cytofix/Cytoperm kit (BD Pharmingen), according to the manufacturer’s protocol.
Cytotoxicity assay
Mice were infected with 200 HAU of influenza A HKx31, as described above. Splenocytes were harvested at various times and restimulated in vitro by the addition of 100 nM H-2Db-restricted peptide NP366–374 to 1-ml cultures containing 5 x 106 spleen cells. On day 5, cells were resuspended to 0.65 ml, and duplicate serial 3-fold dilutions of effectors were performed and assayed for anti-influenza NP-specific CTL activity against 51Cr-labeled EL4 cells pulsed with 50 µM NP366–374 peptide and unpulsed EL4 as control. After 5 h, 70 µl of supernatant was harvested onto 96-well harvest plates (Canberra Packard, Mississauga, Canada) and counted on a Topcount scintillation counter (Canberra Packard). Maximum and spontaneous release was determined from wells that contained 1% SDS or medium alone. The percentage of specific lysis was calculated from the equation: ((experimental 51Cr release – spontaneous 51Cr release)/(maximum 51Cr release – spontaneous 51Cr release)) x 100% = percent specific lysis.
Analysis of IL-2 and IFN- production by CD4 T cells
Cells were isolated from spleen, and RBC were lysed with Tris-NH4Cl solution. Splenocytes (5 x 106 cells) were incubated with 250 HAU of heat-killed (30 min at 56°C) influenza virus for 48 and 96 h, and the supernatants were harvested and analyzed for IL-2 and IFN-, respectively. IL-2 was detected using the indicator cell line CTLL. Serial dilutions of the culture supernatant were prepared in triplicate and incubated with 104 indicator cells in 100 µl in 96-well plates for 24 h. During the final 6 h, the cells were labeled with [3H]thymidine (Amersham Biosciences, Baie d’Urfe, Canada). Cultures were harvested and analyzed on the TopCount 96-well liquid scintillation counter (Canberra Packard). IFN- was detected using ELISA using anti-murine IFN- mAbs from BD Pharmingen, according to the manufacturer’s instructions.
Superantigen responses
Mice were injected i.p. with 3 µg of staphylococal enterotoxin A (SEA) (Toxin Technology, Saratoga, FL), and spleens were harvested 2 or 12 days later and analyzed by flow cytometry, as described previously, for TCR V3 and CD4 or TCR V3 and CD8 cells.
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Results |
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As discussed above, there is evidence that both CD4 and CD8 T cells can express and respond to signals through 4-1BB and OX40. However, the coexpression of 4-1BB and OX40 has not been rigorously tested in vivo. To compare the relative kinetics of 4-1BB and OX40 expression on CD4 and CD8 T cells in vivo, TCR transgenic CD4 or CD8 T cells were transferred into wild-type (WT) mice, and surface phenotype was monitored by flow cytometry at different time points after immunization with Ag plus LPS. The transferred T cells were followed by the expression of the Thy-1.1 marker following transfer into Thy-1.2 congenic recipients. 4-1BB was detected on the transferred CD4 (OT-II) T cells at 12 h through 24 h postimmunization, whereas OX40 was not highly expressed until after 4-1BB levels had dropped, at 48 h (Fig. 1A). The CD8 (OT-I) T cells expressed 4-1BB later, with maximal expression at 24 h, whereas little or no OX40 was detected at any time point (Fig. 1B). Neither OX40 nor 4-1BB was observed on the surface of OT-I or OT-II T cells at 60, 72, or 96 h post-OVA/LPS injection (data not shown). Analysis of Thy-1.1-positive cells for TCR V2 and V5.1 revealed that the majority of the Thy-1.1-positive cells were transgenic T cells (data not shown). Thus, 4-1BB and OX40 are expressed sequentially on CD4 T cells. In contrast, little or no OX40 was detected on CD8 T cells, under conditions in which 4-1BB expression was readily detected. Thus, although OX40 has been detected on CD8 T cells under some circumstances, these results show that, at least under these conditions of antigenic stimulation, CD8 T cells express 4-1BB, but not OX40, and CD4 T cells sequentially express 4-1BB and OX40, with little or no coincident expression.
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To examine the effect of the combination of 4-1BB and OX40 costimulatory pathways on primary expansion of CD4 and CD8 T cells in vivo, WT, OX40L–/–, 4-1BBL–/–, and DKO mice were injected with SEA, and the expansion of V3+ T cells was followed over time by flow cytometry. The frequency of CD4 and CD8 V3+ T cells at the height of the response (day 2) and after contraction of the response (day 12) was indistinguishable between all four groups of mice (Fig. 2). Similar results were obtained when expressed as total cell numbers per spleen (data not shown). The lack of significant differences between the CD4 and CD8 response suggests that neither OX40L, 4-1BBL, nor the combination influences primary T cell expansion in response to superantigen in mice. Because the superantigen response is tested without any additional adjuvant, there may be insufficient induction of TNF family ligands on APC to impact on the response. The intact response to SEA in OX40L–/–4-1BBL–/– mice confirms that T cells develop normally in the absence of the two costimulatory pathways and exhibit normal responsiveness to TCR stimulation in vivo.
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Influenza infection of mice represents a useful model for studying costimulatory requirements of T cells (2). Mice deficient in OX40 show impaired CD4 T cell responses to influenza delivered intranasally (i.n.) with no defects in CD8 T cell responses (14). 4-1BBL–/– mice have decreased CD8 T cell recall responses with no defects in CD4 responses to influenza delivered i.p. (23, 25). Although the i.n. route of immunization, which induces an acute localized infection in the respiratory tract, is the physiological route of infection, we have found that immune responses observed with the less infectious i.p. route of infection are sensitive to costimulation and avoid the complications of inflammation and weight loss associated with the more severe disease observed with i.n. infection. Using this model, we previously determined that 4-1BBL–/– mice showed no difference in initial primary expansion or contraction of the CD8 T cell response, which peaks in the spleen at day 7 postimmunization. However, 4-1BBL–/– mice had decreased CD8 T cell numbers at 3–6 wk after priming and showed decreased secondary responses (25), a defect that is corrected by adding agonistic Abs during the boost, but not the priming phase of the response (43).
To test the combined effects of 4-1BBL and OX40L on influenza responses, DKO, 4-1BBL–/–, OX40L–/–, and WT mice were infected i.p. with influenza A HKx31 and sacrificed at time points representing the peak of primary CD8 T cell expansion (day 7), as well as at day 21, by which time a significant decline in CD8 T cell numbers was previously noted in 4-1BBL–/– mice (25). Splenocytes were analyzed for expansion of NP366–374-specific T cells using Db/NP366–374 tetramers. By day 7, 
6% of CD8 T cells were specific for NP366–374 (Fig. 3A), with no significant difference between the four genotypes of mice. There were no significant differences in the number of splenocytes recovered between the different mice, and, as a result, when the percentages were converted to absolute cell numbers, similar results were obtained (data not shown). Thus, the initial expansion of CD8 T cells is not affected by the lack of 4-1BB or OX40 ligation. Following restimulation with NP366–374 peptide, the number of IFN--producing cells was also similar between the four groups of mice (Fig. 3B). Thus, both the primary expansion and the development of effector function of CD8 T cells are unaffected by the lack of 4-1BB and OX40 costimulation.
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-producing cells, whereas OX40L–/– and WT mice had significantly more at 0.8% (p < 0.02; Fig. 3D).
After restimulation with peptide for 5 days, the recall CTL activity of T cells primed in DKO and 4-1BBL–/– mice was reduced compared with OX40L–/– and WT animals (Fig. 3G). There were no significant differences between 4-1BBL–/– and DKO, or between OX40L–/– and WT animals with respect to the number of Ag-specific CD8 T cells, their ability to produce IFN-, or their ability to kill targets.
To compare the importance of each molecule in the secondary response, mice were rechallenged with a serologically distinct PR8 strain, 21 days after priming. As before, we quantitated the proportion of CD8 T cells that were specific for the NP366–374 peptide, 7 days after reinfection. At this time point, DKO and 4-1BBL–/– animals had 8 and 9% influenza-specific CD8 T cells, whereas the OX40L–/– and WT mice had significantly more cells at 13 and 14%, respectively (p < 0.003; Fig. 3E). We also analyzed the effector function of these T cells by determining their ability to produce IFN- in response to NP366–374 peptide. Both DKO and 4-1BBL–/– animals had 9% of CD8 cells producing IFN-, and the OX40L–/– and WT mice had significantly more at 15% (p < 0.01; Fig. 3F). The cytolytic capacity also followed the same trend as the tetramer-specific T cell numbers. There were no differences between DKO and 4-1BBL–/– or between OX40L–/– and WT animals, and the animals that were missing 4-1BBL had similarly decreased cytolytic activity regardless of the presence of OX40L (Fig. 3H). These results support the conclusion that 4-1BB/4-1BBL interactions are required for optimal secondary CD8 T cell responses, whereas OX40/OX40L interactions are not. As 4-1BBL and DKO mice were indistinguishable in all parameters measured, there appears to be no compensation between these two TNFR family costimulatory pathways with respect to CD8 T cell responses.
OX40/OX40L interactions are required for optimal CD4 recall response to influenza
As discussed above, both 4-1BB and OX40 can affect CD4 T cell responses in some models. Therefore, we analyzed the CD4 responses to influenza in the four groups of mice. Splenocytes isolated on day 21 postinfection were incubated with heat-inactivated influenza virus. Heat inactivation renders the virus noninfectious and targets the virus to the MHC class II presentation pathway for activation of CD4 T cell responses. The level of IL-2 and IFN- in the supernatants was used as an indicator of activation of influenza-specific CD4 T cells. The absence of 4-1BBL had no significant impact on either IL-2 or IFN- production (Fig. 4, A and C). In contrast, OX40L–/– and DKO mice had significantly reduced levels of both IL-2 and IFN- compared with the WT and 4-1BBL–/– mice (p < 0.01; Fig. 4, A and C). A similar trend was observed when the mice were rechallenged with the PR8 strain of influenza virus and analyzed 7 days later. Mice deficient in OX40L (OX40L–/– and DKO) have a defect in the CD4 response, as indicated by the significantly lower levels of IL-2 and IFN- (Fig. 4, B and D; p < 0.01). Again, the DKO mice do not have a greater reduction in the CD4 response compared with the OX40L–/– animals. Thus, only OX40 contributes to the recall CD4 T cell response to influenza.
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One of the shortcomings of the influenza model system is that it is difficult to directly enumerate the responding CD4 T cells early in the primary response. To overcome this shortcoming, an adoptive transfer model with CD4 OT-II transgenic cells was used. T cells were purified from OT-II mice, and each animal received 2.5 x 106 OT-II cells. Twenty-four hours later, mice were injected s.c. with OVA/LPS. One, 3, and 8 days later, splenocytes were stained for TCR V2, TCR V5.1, and CD4, and analyzed by FACS to determine the extent of OT-II T cell expansion. At the peak of the response (day 3), there were reduced numbers of OT-II cells in 4-1BBL–/– and DKO mice, with no differences detected between OX40L–/– and WT, or 4-1BBL–/– and DKO mice (Fig. 5A). These results suggest that OX40/OX40L interactions are dispensable for the primary accumulation of CD4 T cells and that 4-1BB/4-1BBL interactions do not compensate for the loss of OX40L.
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Discussion |
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With OVA/LPS immunization, which involves transient activation via a nonreplicating Ag, 4-1BB and OX40 are not extensively coexpressed in vivo (Fig. 1). On CD4 T cells, substantial OX40 expression was only detected after the expression of 4-1BB had returned to baseline, at 48 h. 4-1BB is expressed before the T cells start dividing (31), whereas OX40 is expressed after division has commenced (data not shown) (31). This implies that a T cell could first receive a 4-1BBL signal and then disengage, undergo division, and re-engage an APC. Whether it re-engages the same APC or a different one remains to be determined. The discovery of CD4+CD3– accessory cells that are low in CD80, CD86, and 4-1BBL, but high in OX40L, suggests that OX40 signals can be delivered from a different APC (44). 4-1BB was expressed on CD8 T cells 24 h post-Ag injection, but no OX40 was observed either at the time of 4-1BB expression, or afterward when the cells became CD44high (data not shown) (31). OX40 expression has been documented on in vitro stimulated CD8 T cells (5, 45, 46, 47), but it has not been shown on CD8 T cells directly ex vivo from a mouse. The discrepant results might be due to different levels of antigenic stimulation achieved in the different models, which in turn could impact on the levels of OX40 and its ligand that are induced. Nevertheless, we show that activated CD8 cells express little or no OX40 under conditions that up-regulate 4-1BB, CD69, and CD44. Thus, under conditions of limited antigenic stimulation in vivo, OX40 and 4-1BB are not expressed to a significant extent on the same cells and appear to function independently in the immune response in the spleen. It should be pointed out, however, that under conditions of chronic or prolonged infection or inflammation, there may be more sustained expression of TNFR family costimulatory molecules (30, 48).
CD4 T cell help is required to maintain CD8 T cell numbers at the end of the primary response to influenza, and recall CD8 T cell responses to influenza are reduced in MHC II-deficient animals (49, 50). Therefore, one might have expected OX40 deficiency to impair CD8 responses due to decreased help. CD4 help for CD8 memory responses is important during CD8 T cell priming, but dispensible during the secondary response (51, 52). Because OX40L deficiency impairs secondary, but not primary CD4 T cell expansion, this most likely explains the failure to see an impact of OX40 on help for CD8 T cell responses. The finding that OX40/OX40L appears to have no impact on the primary response of OT-II T cells even in the absence of 4-1BBL further supports the idea that OX40L is not important during T cell primary expansion. Because there was no detectable secondary CD4 T cell response of OT-II T cells in OX40L–/– mice, it was not possible to assess whether there is synergy in the contribution of OX40L and 4-1BBL to CD4 secondary responses. However, it is clear from comparison of the single knockout animals in the same experiment that OX40 costimulation of CD4 recall is quantitatively more important than the effect of 4-1BB on this response.
Two studies have suggested a potential role for 4-1BB and OX40 in responses to superantigen. In particular, agonistic anti-OX40 Ab when combined with LPS and superantigen allows maintenance of an expanded CD4 T cell population (9). Similarly, agonistic anti-4-1BB Abs can result in increased expansion and survival of T cells following superantigen administration in mice, with greater effects on CD8 T cells (21). However, in the present study, we found no evidence of a role for endogenous OX40L or 4-1BBL in primary expansion in response to superantigen.
The lack of impact of the OX40L deficiency on the CD8 response to influenza is consistent with previous findings by Kopf et al. (14), who used the i.n. model of infection to show a similar defect in CD4 T cell responses, as we observe with the i.p. model. Our finding that DKO mice have a similar defect as 4-1BBL–/– animals confirms that OX40L–/– is dispensable for the CD8 response to influenza, and that this is not merely due to compensation by 4-1BB/4-1BBL.
Three studies have shown that CD8 TCR transgenic OT-I T cells respond to OX40 costimulation in vivo (6, 32, 33). In most of the experiments, anti-OX40 was used to enhance signals through OX40, which most likely amplifies effects of this signaling pathway over that seen when endogenous ligand is removed. However, Bansal-Pakala et al. (32) observed defects in OX40–/– OT-I T cell expansion when mice were immunized with peptide in CFA in the absence of added anti-OX40 Ab. Thus, as observed in vitro, it appears that if a sufficiently strong antigenic signal is given, then CD8 T cells can up-regulate and respond to OX40 stimulation.
In terms of CD4 responses, OX40/OX40L interactions are required for the establishment of a robust CD4 memory pool that can vigorously respond to rechallenge with influenza virus or protein Ag. The adoptive transfer model also reveals a dependence on 4-1BBL for the CD4 recall response, but it is relatively minor compared with the requirement for OX40. The mice that lacked OX40L (OX40L–/– and DKO) had a completely absent secondary expansion of OT II cells, whereas the 4-1BBL–/– showed delayed and reduced expansion of OT-II cells upon rechallenge. Furthermore, the influenza model failed to reveal any defects in CD4 T cell responses in the absence of 4-1BBL.
Some studies have shown quantitative defects in Ab responses in the absence of OX40 (16, 44). However, most studies have shown that OX40 and 4-1BB costimulatory interactions are dispensible for humoral immunity (13, 14, 15, 25). Consistent with these findings, we observed no defect in influenza-specific Ab production or class switch to IgG1 or IgG2a in any of the four genotypes of mice (data not shown). The lack of effect of removing OX40L on the primary CD4 or Ab responses is not due to compensation by 4-1BB because the DKO animals do not show a defect in the expansion of transferred CD4, in sAg-activated CD4 T cells, or Ab production, further supporting the idea of distinct functions for the two costimulatory receptors.
In conclusion, our results show that 4-1BB and OX40 can be expressed separately on T cells in vivo, with OX40 restricted to CD4 T cells and its expression delayed compared with 4-1BB. By comparing 4-1BB/4-1BBL and OX40/OX40L in the same model, the data clearly show distinct roles for the two costimulatory pathways in the development of CD8 and CD4 recall responses, with little or no effect on primary expansion of T cells. Analysis of mice deficient in both costimulatory pathways revealed that the two costimulatory pathways function independently and nonredundantly to facilitate robust CD8 and CD4 T cell responses.
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Acknowledgments |
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Footnotes |
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1 This research was supported by a grant from the Canadian Institutes of Health Research (to T.H.W.). 
2 Current address: Division of Immunology and Genetics, The John Curtin School of Medical Research, The Australian National University, P.O. Box 334 Mills Road, Canberra, Australia 2601.
3 Address correspondence and reprint requests to Dr. Tania H. Watts, Department of Immunology, University of Toronto, 1 King’s College Circle, Toronto, Ontario, M5S 1A8. E-mail address: tania.watts{at}utoronto.ca
4 Abbreviations used in this paper: DKO, double knockout; HAU, hemagglutinating unit; i.n., intranasal; NP, nuclear protein; SEA, staphylococcal enterotoxin A; WT, wild type.
Received for publication July 9, 2004. Accepted for publication August 17, 2004.
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 M. D. Vu, X. Xiao, W. Gao, N. Degauque, M. Chen, A. Kroemer, N. Killeen, N. Ishii, and X. Chang Li OX40 costimulation turns off Foxp3+ Tregs Blood, October 1, 2007; 110(7): 2501 - 2510. [Abstract] [Full Text] [PDF]
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S.-J. Lee, R. J. Rossi, S.-K. Lee, M. Croft, B. S. Kwon, R. S. Mittler, and A. T. Vella CD134 Costimulation Couples the CD137 Pathway to Induce Production of Supereffector CD8 T Cells That Become IL-7 Dependent J. Immunol., August 15, 2007; 179(4): 2203 - 2214. [Abstract] [Full Text] [PDF]
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S. Fuse, S. Bellfy, H. Yagita, and E. J. Usherwood CD8+ T Cell Dysfunction and Increase in Murine Gammaherpesvirus Latent Viral Burden in the Absence of 4-1BB Ligand J. Immunol., April 15, 2007; 178(8): 5227 - 5236. [Abstract] [Full Text] [PDF]
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 I. Houtenbos, T. M. Westers, A. Dijkhuis, T. D. de Gruijl, G. J. Ossenkoppele, and A. A. van de Loosdrecht Leukemia-Specific T-Cell Reactivity Induced by Leukemic Dendritic Cells Is Augmented by 4-1BB Targeting Clin. Cancer Res., January 1, 2007; 13(1): 307 - 315. [Abstract] [Full Text] [PDF]
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S.-W. Lee, Y. Park, A. Song, H. Cheroutre, B. S. Kwon, and M. Croft Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses J. Immunol., October 1, 2006; 177(7): 4464 - 4472. [Abstract] [Full Text] [PDF]
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M. D. Vu, M. R. Clarkson, H. Yagita, L. A. Turka, M. H. Sayegh, and X. C. Li Critical, but Conditional, Role of OX40 in Memory T Cell-Mediated Rejection J. Immunol., February 1, 2006; 176(3): 1394 - 1401. [Abstract] [Full Text] [PDF]
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S. Murata, B. H. Ladle, P. S. Kim, E. R. Lutz, M. E. Wolpoe, S. E. Ivie, H. M. Smith, T. D. Armstrong, L. A. Emens, E. M. Jaffee, et al. OX40 Costimulation Synergizes with GM-CSF Whole-Cell Vaccination to Overcome Established CD8+ T Cell Tolerance to an Endogenous Tumor Antigen J. Immunol., January 15, 2006; 176(2): 974 - 983. [Abstract] [Full Text] [PDF]
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E. Y. Kim, J. J. Priatel, S.-J. Teh, and H.-S. Teh TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo J. Immunol., January 15, 2006; 176(2): 1026 - 1035. [Abstract] [Full Text] [PDF]
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L. Serghides, J. Bukczynski, T. Wen, C. Wang, J.-P. Routy, M.-R. Boulassel, R.-P. Sekaly, M. Ostrowski, N. F. Bernard, and T. H. Watts Evaluation of OX40 Ligand as a Costimulator of Human Antiviral Memory CD8 T Cell Responses: Comparison with B7.1 and 4-1BBL J. Immunol., November 15, 2005; 175(10): 6368 - 6377. [Abstract] [Full Text] [PDF]
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B. Y. Ma, S. A. Mikolajczak, A. Danesh, K. A. Hosiawa, C. M. Cameron, A. Takaori-Kondo, T. Uchiyama, D. J. Kelvin, and A. Ochi The expression and the regulatory role of OX40 and 4-1BB heterodimer in activated human T cells Blood, September 15, 2005; 106(6): 2002 - 2010. [Abstract] [Full Text] [PDF]
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J. Hendriks, Y. Xiao, J. W. A. Rossen, K. F. van der Sluijs, K. Sugamura, N. Ishii, and J. Borst During Viral Infection of the Respiratory Tract, CD27, 4-1BB, and OX40 Collectively Determine Formation of CD8+ Memory T Cells and Their Capacity for Secondary Expansion J. Immunol., August 1, 2005; 175(3): 1665 - 1676. [Abstract] [Full Text] [PDF]
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