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Cell Antigens1
* Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia;
Centre for Inflammatory Disease, Monash University Department of Medicine, Monash Medical Center, Clayton, Victoria, Australia;
Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia; and
Section of Immunobiology and Howard Hughes Medical Institute, Yale University, New Haven, CT 06520
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we examined the nature of help provided by activated CD4 T cells for induction of CTL-mediated pancreatic islet tissue destruction. In contrast to recent reports (18, 19), we show that Th cells were essential for in vivo induction of primary effector CTL, and that CD40 signaling of the dendritic cell (DC)4 was critical. In addition, our findings indicate that once activated, Th cells may signal CD40 on the DC without the need to see Ag on this same cell. These studies define important considerations for CTL immunotherapy by adoptive transfer, as might be used for the treatment of cancer (24) or virus-infected immunodeficient patients (25, 26).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All mice were used between 6 and 12 wk. All mice, including C57BL/6 (B6) and bm1 mice, were bred and maintained at the Walter and Eliza Hall Institute of Medical Research. Rag-1 knockout mice (27), IL-2 knockout mice (28), class II knockout mice (29), OVA-specific class II-restricted TCR transgenic (OT-II) mice (30), CD40 ligand knockout mice (31), and OVA-specific class I-restricted TCR transgenic (OT-I) mice (32) have been previously described. OT-II mice were on a pure B6 background. Rag-1 knockout mice, class II knockout mice, and IL-2 knockout mice were derived from 129 background mice and backcrossed at least 10 times to a B6 background. CD40 ligand knockout mice were derived on a 129 background and backcrossed at least eight times to a B6 background. All studies were performed according to approved institutional protocols.
Generation of bone marrow chimeras
Recipient mice, 
8 wk old, were irradiated with a single dose of 900 cGy or two doses of 550 cGy 3 h apart. After an additional 4 h, mice were injected i.v. with 5 x 106 T-depleted bone marrow cells. For mixed bone marrow chimeras, 2.5–5.0 x 106 cells of each type were coinjected. Bone marrow was depleted of T cells by treatment with Thy-1-specific (J1j), CD8-specific (3.168), and CD4-specific (RL172) mAb, followed by rabbit complement. The day after reconstitution, mice were injected with 100 µl of Thy-1-specific T24 ascites to deplete remaining host and donor T cells. Chimeras were allowed to reconstitute for at least 7 wk before use. Reconstitution of blood lymphocyte populations in mixed chimeras was confirmed by FACS analysis of blood using Kb-specific and I-Ab-specific mAb.
Preparation of responder T cells, adoptive transfer, and diabetes monitoring
OT-I and OT-II cells were prepared as described (33, 34). Briefly, OT-I cells were derived from the spleen and lymph nodes (LN) of Rag-1-deficient OT-I mice. These cells were treated with RL172 (anti-CD4) and J11d (anti-heat-stable Ag) for 30 min on ice, centrifuged, and then depleted by treatment with rabbit complement for 30 min at 37°C. For OT-II cells, LN were removed from OT-II mice, and single cells were treated with 3.168 (anti-CD8) and J11d and then complement, as above. Cells were adoptively transferred by i.v. injection into the lateral tail vein. Recipient mice were monitored for diabetes from day 5 after transfer for at least 4 wk by urine glucose testing. Animals were considered diabetic after 2 consecutive days with readings 
55 mmol/L.
Fluorescent labeling of T cells
CFSE labeling was performed, as previously described (35). Briefly, semipurified T cells (OT-I or OT-II) were resuspended in PBS containing 0.1% BSA (Sigma-Aldrich, St. Louis, MO) at 107 cells/ml. For fluorescence labeling, 1 µl of CFSE (Molecular Probes, Eugene, OR) stock solution (5 mM in DMSO) was incubated with 107 cells for 10 min at 37°C.
Flow cytometry
Before adoptive transfer, or culture in vitro, OT-I and OT-II cell preparations were analyzed by flow cytometry using a FACScan or LSR (BD Biosciences, Mountain View, CA), as previously described (33, 35).
Tetramer staining of OT-I cells
Four days after adoptive transfer of OT-I (2.5 x 105) with or without activated OT-II cells (2 x 105) or FGK45 Ab (100 µg per day on days 0–2), single cell suspension was obtained from spleen, inguinal, axillary, brachial, and mesenteric LN of recipient rat insulin promoter (RIP)-OVAhi mice. Equal fractions of these suspensions were stained with Kb-OVA257–264 tetramer-PE conjugate at 37°C for 60 min, washed, and stained with CD8 FITC (BD PharMingen, San Diego, CA). To derive the total number of OT-I cells per mouse, the proportion of Kb-OVA257–264 tetramer-positive cells of the total CD8+ T cells in test mice minus the background staining in uninjected mice was multiplied by the proportion of CD8+ T cells in total live cells and the number of live cells.
Activation of OT-II cells
For activation of OT-II cells in vitro, splenocytes from OT-II mice (2 x 106/ml) were cultured in modified RPMI 1640 culture medium containing 10% FCS, glutamine, antibiotics, and 1 mg/ml OVA. After culture for 4 days in a humidified 5% CO2-in-air incubator, cells were washed and enriched by complement depletion, as described above. The number of specific T cells was determined by flow cytometric analysis after culture. When IL-2 knockout OT-II cells were used, 20 U/ml IL-2 was added at the beginning of culture.
Statistical analysis
Statistical significance of the difference between groups was determined by 
2 test using SPSS 11.0 (SPSS, Chicago, IL). Differences were considered significant at p < 0.05.
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Results |
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To examine the requirements for induction of a CD8 T cell response capable of pancreatic islet destruction, we adoptively transferred naive OVA-specific CD8 T cells from the OT-I transgenic line into RIP-OVAhi transgenic mice, which express secreted OVA in the pancreatic islet 
cells (36). OT-I cells did not cause diabetes, even when as many as 10 million cells were adoptively transferred (Table I, Expt. A). To determine whether OVA-specific CD4 Th cells derived from the OT-II transgenic line could help OT-I cells cause islet destruction, RIP-OVAhi mice were adoptively transferred with naive OT-I and naive OT-II cells, and diabetes was monitored (Table I, Expt. B). Interestingly, this did not lead to diabetes induction, despite transferring 10-fold more OT-I cells than previously shown to cause diabetes in the RIP-mOVA transgenic model (34) (Table I, Expt. C). To explain the differences between these two transgenic models, we examined the proliferation of CFSE-labeled OT-I and OT-II cells in the pancreatic LN of RIP-OVAhi mice. Although OT-I cells proliferated very well, OT-II cells showed a detectable, but very poor response (Fig. 1A). This contrasts our previous observations with the RIP-mOVA mice, in which both T cell subsets were efficiently activated (34). Differences in OT-II activation are most likely explained by a hier level of Ag expression in the RIP-mOVA line (37). These data suggest that the poor activation of naive OT-II cells in RIP-OVAhi mice might explain their failure to help OT-I cells cause diabetes.
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It should be noted that activated OT-II cells could cause diabetes when transferred alone, but this required at least 107 cells and was never seen with 2 x 106 cells (right three columns in Fig. 1B). For the remainder of this study, we used the combination of activated OT-II cells and naive OT-I cells to examine the underlying mechanism(s) of help for the induction of diabetes in RIP-OVAhi mice.
To establish the minimum number of OT-I cells required to cause diabetes, these cells were titrated while the number of activated OT-II cells was kept constant (Fig. 1C). This indicated that as few as 2.5 x 103 naive OT-I cells coinjected with 2 x 105 activated OT-II cells caused diabetes in most (five of seven) mice. The relatively small numbers of cotransferred OT-I and OT-II cells required to cause islet destruction indicated a cooperative interaction between the two subsets.
OT-I cells are responsible for directly recognizing and destroying islet cells
To confirm that the CD8 T cells were responsible for directly destroying islet cells, chimeric mice were generated in which the CD8 T cells could not recognize OVA presented by islet cells, but could recognize OVA presented on bone marrow-derived DCs. This required that we crossed RIP-OVAhi mice to bm1 mice (RIP-OVAhi.bm1) and then generated B6
RIP-OVAhi.bm1 bone marrow chimeras. Because bm1 mice cannot present OVA to OT-I cells (38), such chimeras would have the capacity to cross-present class I-restricted OVA determinants on those Kb molecules expressed by their B6 DC, but would not be able to present OVA on the Kbm1 molecules expressed by their bm1 islet cells. In contrast, both bm1 and B6 mice express the same MHC class II molecule, I-Ab, and so all class II-expressing cells would have equal potential to present to OT-II cells. When these B6RIP-OVAhi.bm1 chimeras, and B6RIP-OVAhi.B6 control chimeras, were coinjected with activated OT-II cells and naive OT-I, only the B6RIP-OVAhi.B6 chimeras became diabetic (Table II). Thus, direct recognition of islet cells by OT-I cells was essential for islet destruction and diabetes onset.
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To directly demonstrate the islet tissue-specific response was induced by cooperation between the activated OT-II and OT-I cells in a way that improved the OT-I response, rather than simply by adding the destructive effects of both cell populations together, we examined the expansion of OT-I cells after transfer in the presence or absence of activated helpers. This showed that the help provided by activated OT-II cells led to the generation of 152 ± 98 x 104 OT-I cells in the spleen and LN of RIP-OVAhi mice on day 4, compared with only 17 ± 13 x 104 cells when OT-I cells were transferred alone (Fig. 1D). This indicates a dramatic increase in the number of OT-I effectors produced when provided with OT-II help. Examination of pancreas sections for infiltrating cells showed little evidence of either OT-I or OT-II cells in the pancreas when each population was transferred alone, whereas extensive infiltration could be seen as early as day 3 when these cells were cotransferred (data not shown). Together, these data indicate a cooperative interaction between the OT-I and OT-II cells, supporting the view that the CD4 T cells provide help to the CD8 T cells, which then are essential to cause islet destruction.
Corecognition of Ag on the same DC is not required
In previous studies, we showed that help was essential for inducing a memory CTL response by cross-priming with foreign Ag (11), and our studies together with others suggested that CD4 helper cells mediated their help by signaling CD40 on the DC, in a process in which both CD4 and CD8 T cells interacted with the same DC (11, 20, 21, 22). To determine whether CD4 help occurred in a similar way for conversion of tolerance to a tissue-destructive response, we first tested whether OT-I and OT-II cells needed to recognize Ag on the same DC. This was tested by generating chimeric RIP-OVAhi mice that were either reconstituted with B6 bone marrow (B6B6), or a combination of class II-deficient (I-A–/–) bone marrow plus bm1 bone marrow ((I-A–/– + bm1)B6). In the mixed bone marrow chimeras, two types of DC were produced: one that could present OVA to OT-I cells, but not OT-II cells (I-A–/– DC), and one that could present to OT-II cells, but not OT-I cells (bm1 DC). To determine whether the reconstitution protocol was efficient enough to replace B6 DC with those derived from the donor bone marrow, we also generated chimeric mice that were bm1B6. These mice should not become diabetic, as OT-I cells cannot be activated by bm1 DC. When these three sets of chimeras were coinjected with activated OT-II cells and naive OT-I cells, B6B6 chimeras and mixed bone marrow chimeras virtually all became diabetic, whereas bm1B6 chimeras rarely did so (Table III). These data indicated that for induction of an islet tissue-destructive response, the CD4 and CD8 T cells were not required to recognize Ag on the same DC.
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The above findings raised the question of whether activated OT-II cells needed to see Ag at all, after their initial activation. To test this, we crossed RIP-OVAhi mice to MHC II I-A–/– (I-A–/–) mice and generated a class II-deficient mouse line termed RIP-OVAhi.I-A–/–. These RIP-OVAhi.I-A–/– mice and their class II-expressing heterozygous littermates were injected with activated OT-II cells together with naive OT-I cells. Although none of 10 class II-deficient RIP-OVAhi mice succumbed to disease, 13 of 14 control heterozygous (I-A+/–) or wild-type mice became diabetic. This indicated that class II-restricted recognition was important for activated OT-II cells to provide help.
CD40 ligand is an important helper factor
To determine whether CD40 ligand was an important component of CD4 T cell help in this model, OT-II mice were crossed to CD154 (CD40 ligand) knockout mice. RIP-OVAhi mice were coinjected with naive OT-I cells plus activated OT-II cells deficient for CD154 (first two rows of Table IV). This showed that CD40 signaling by helper cells was an important component of help, with few (4 of 28) mice becoming diabetic when OT-II cells failed to express CD154. To ensure that the CD154-deficient helper cells were fully competent helpers other than their failure to express CD154, three additional groups of mice were given OT-I cells together with either: 1) an anti-CD40 agonistic mAb, FGK45, alone; or 2) CD154-deficient OT-II cells plus FGK45 mAb; or 3) CD154-deficient OT-II cells plus an isotype control mAb, GL117 (last three rows of Table IV). This experiment showed that CD40 signaling alone could not provide help, but that in combination with CD154-deficient helpers it was very efficient. It also implied that the CD154-deficient helpers provided additional helper factors essential to induce autoimmunity. As shown in Fig. 1D, coadministration of the anti-CD40 mAb FGK45 with OT-I cells also failed to generate the extensive expansion of OT-I cells seen in the spleen and LN when activated helpers were given.
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Together, the above data suggested that linked MHC-restricted help was not required, but that a CD154-dependent helper signal was important. This raised the question of where the CD154 signal was directed: was it to the DC presenting to OT-I cells or to the DC presenting to activated OT-II cells? To test whether a CD154 signal directed to the DC presenting to OT-I cells was essential, we generated chimeric RIP-OVAhi mice that were either reconstituted with a combination of I-A–/–CD40–/– double-knockout bone marrow plus bm1 bone marrow ((I-A–/–CD40–/– + bm1) B6) or a combination of I-A–/– bone marrow plus bm1 bone marrow ((I-A–/– + bm1)B6). In the former mixed bone marrow chimeras, the DC presenting to OT-I cells were unable to receive a CD40 signal. As a result, (I-A–/–CD40–/– + bm1)B6 RIP-OVAhi chimeras were unable to develop diabetes (Fig. 2A). This supported the idea that the DC presenting to OT-I cells required a CD40 signal (Fig. 2B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cell destruction and diabetes by CTL effectors. In adoptive transfer experiments, we showed that help, in the form of activated CD4 T cells, was required for islet-specific CTL to cause diabetes in RIP-OVAhi mice (Fig. 1B). Using chimeric mice, we provided evidence that without recognition of islet class I molecules, diabetes did not ensue (Table II), supporting the view that CTL were the final effectors in this model. It remains possible that CD4+ OT-II cells provided some effector function, but clearly, they were excellent helpers, but poor effectors. This was illustrated by the observation that as few as 2 x 104 OT-II cells could help OT-I cells cause diabetes (Fig. 1C), whereas transfer of 107 OT-II cells alone was needed to cause disease (Fig. 1B). Further evidence that OT-II cells were not contributing to effector function was provided by the observation that activated OT-II cells deficient in the effector cytokines IFN-
or TNF-
were equivalent to wild-type OT-II cells in their ability to help OT-I cause diabetes in this model (data not shown). Importantly, our data argue that some primary CTL effector responses can be highly dependent upon CD4 T cell help (in this case activated helpers), contrasting recent suggestions that memory CTL responses are dramatically dependent on CD4 T cell help, while primary responses show minimal dependence (18, 19). We have also extended these findings to two other models, i.e., priming with HSV type 1 and with OVA-coated spleen plus LPS. In both cases, primary CTL responses were highly dependent on CD4 T cell help (data not shown). Together, these findings suggest that help can play an important role in primary CTL immunity.
Several reports have indicated that helper cells and CTL must interact with the same APC for help to be effectively supplied (11, 39, 40). This corecognition was reported to relate to a requirement for the helper cell to signal CD40 on the APC, licensing it for priming naive CTL. More recently, however, it has been suggested that signaling of CD40 on the CTL may be critical for induction of memory CTL responses (19). To determine whether similar rules applied in the RIP-OVAhi autoimmunity model, we used mixed bone marrow chimeras to examine diabetes induction when activated helpers and naive CTL were unable to recognize Ag on the same DC (Table III). This clearly showed that recognition of Ag on the same DC was not essential for helper function. A lack of requirement for linked recognition was unlikely to be explained simply by an excess of helper cells, because the dose of helpers used was at the threshold for induction of diabetes even when unmanipulated RIP-OVAhi mice were used as recipients (Fig. 2B). This finding initially led us to believe that there was no corecognition of the DC by the helper and naive CTL, and that the help was more likely supplied as a soluble factor, such as IL-2. However, examination of the requirement for CD154 expression by the Th cells indicated that CD40 signaling was important for the islet-destructive response. This raised the question of where the CD40 signal was necessary. By generating a second series of mixed bone marrow chimeras in which the CD4 T cells and CD8 T cells could not recognize Ag on the same DC, and in which the DC presenting to the CD8 T cells was deficient for CD40, it was possible to demonstrate CD40 ligand was required to signal CD40 on the DC presenting to the CD8 T cell (Fig. 2). This model, therefore, led us to the novel understanding that CD4 and CD8 T cells were required to interact with the same DC, but that the CD4 T cell did not necessarily have to see Ag on that DC. This is an important observation, as it suggests that CD4 T cells can be activated on one DC and then provide help to other DC they may encounter. This could provide a very efficient and rapid means for amplifying a CTL response. Lack of a requirement for secondary cognate interactions means that once a CD4 T cell is activated by one DC, it can move to adjacent DC and rapidly signal CD40 without awaiting a second TCR signal via MHC and Ag. It is unlikely in this case that CD40 signaling is critical for DC trafficking to the LN (41), as Ag presentation is constitutive (33) and not apparently dependent on inflammatory signals.
In several earlier studies examining the helper requirement for CTL priming, helper cells were required to recognize Ag on the same DC as seen by the CTL (11, 39, 40). Why was there no such requirement in our current model? Earlier studies examined CTL generation in the spleen rather than LN, which due to architectural differences may have different requirements for provision of help. Alternatively, our current studies use activated Th cells, which are likely to provide help much earlier in the response, and may have fewer requirements than naive helpers for up-regulating their CD154 signal. If full activation of naive helpers requires that CTL must also deliver signals to the DC (42), then this could explain a need for corecognition of Ag on the same DC when starting with naive helpers.
The lack of a requirement for activated OT-II cells to recognize Ag when delivering their CD154 signal is unlikely to be because the number of OT-II cells adoptively transferred is excessive. First, the numbers are relatively low, especially when considering <20% are likely to survive adoptive transfer. Second, examination of Fig. 1B shows that 2 x 105 activated OT-II cells are close to the minimum number that can help even when the helpers are able to corecognize Ag with OT-I cells on the same B6 APC. Thus, this is a minimal number of OT-II cells that can provide help whether they can see Ag on the CTLs APC or not.
Based on the fact that neither agonistic mAb to CD40 nor CD154-deficient helpers could provide help alone, but could act in concert, additional helper factors must be operating in this model. In an attempt to identify these, OT-II cells deficient in the ability to produce IL-2 were examined. This led to a 41% reduction in the frequency of diabetes (data not shown), suggesting IL-2 was a minor helper factor, but that other factors most likely exist. Interestingly, neither deficiency in IFN- nor TNF- production by the helper population affected the frequency of diabetes (data not shown).
It is interesting to note that using a related model, Sherman and colleagues (43) also reported that a CD40-specific agonistic mAb could not fully substitute for help, although it allowed expansion of CTL in the draining LN. They suggested that additional helper factors were important for CTL differentiation rather than expansion. Although we too see effective expansion of CTL in the draining LN after administration of CD40-specific agonistic mAb (data not shown), there is a vast difference in the subsequent expansion of these cells in the spleen compared with CTL receiving full helper activity (Fig. 1D). This suggests that additional factors such as IL-2 may also be critical for full CTL expansion as well as differentiation.
These studies highlight the strong influence of CD4 T cell help on the generation of CTL immunity to self Ags. It is likely that these findings will also be applicable to the immunotherapeutic generation of CTL responses for antitumor immunity or antiviral immunity in selected patients (24, 25, 26). Our studies emphasize the critical role of helpers in driving efficient primary CTL effector responses, suggesting that adoptive transfer approaches designed to use CTL as the final effectors would be wise to consider coprovision of activated CD4 T cell help. As shown in this study, Ag-specific helpers are likely to be more efficient than nonspecific helper, because recognition of class II in vivo is essential. However, the ability of activated CD4 T cells to provide CD40-mediated help without seeing Ag on the same APC as the CTL indicates that the Ag specificity of the CD4 T cells need not be the same as the CTL, but could be directed to a vaccinating Ag-like diphtheria toxin. These studies further confirm the importance of CD40 signaling for CTL generation, but additionally emphasize the importance of yet undefined helper factors and IL-2 that together with this signal are critical for full CTL effector activity.
In summary, this study provides evidence that the effector phase of a CTL response may be influenced by the availability of help. In addition, we show that CD154 signaling of CD40 is an important helper signal provided by CD4 T cells in vivo for the induction of effector CTL. Furthermore, we show that the signal to CD40 must be directed to the DC presenting to the naive CTL, and that activated CD4 T cells need not recognize Ag on this DC to signal CD40. These studies have advanced our understanding of the helper requirements for potential manipulation of several situations, including: 1) enhancing the effector function of adoptively transferred tumor-specific CTL used in the treatment of cancer; 2) in the provision of CTL immunity in immunodeficient individuals, such as those infected with HIV or receiving immunosuppression following organ or bone marrow transplantation; and 3) for developing approaches to impair CTL-mediated autoimmunity, such as type 1 diabetes.
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Acknowledgments |
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Footnotes |
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2 G.M.N.B. and M.L. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. William R. Heath or Dr. Georg M. N. Behrens, Immunology Division, Walter and Eliza Hall Institute, 1G Royal Parade, Parkville 3050, Victoria, Australia. E-mail address: heath{at}wehi.edu.au or behrens{at}wehi.edu.au
4 Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; OT-I, OVA-specific class I-restricted TCR transgenic; OT-II, OVA-specific class II-restricted TCR transgenic; RIP, rat insulin promoter.
Received for publication December 15, 2003. Accepted for publication February 19, 2004.
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- and -chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76:34.[Medline]
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, Represent the percentage of diabetic RIP-OVAhi recipients. C, Titration of OT-I cells cotransferred with a constant number of activated OT-II cells. A total of 2 x 105 activated OT-II cells was coinjected with graded doses of naive OT-I cells into RIP-OVAhi mice. These mice were then monitored for diabetes. D, H-2Kb-OVA tetramers were used to quantitate OT-I cells in the spleen and LN 4 days after adoptive transfer into RIP-OVAhi mice. OT-I cells were either given alone or together with activated OT-II cells or anti-CD40 Ab (FGK45).