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Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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As discussed previously (4, 10, 11), under normal T-replete conditions, IL-7 probably acts mainly as a survival factor and keeps naive resting T cells alive by blocking the onset of apoptosis. In normal animals, the background concentration of IL-7 in the lymphoid tissues is presumably maintained at a low, though significant, level by continuous absorption by T cells and other cells. With severe T depletion, we envision that available IL-7 levels rise and thereby augment TCR signaling in residual T cells contacting self-MHC/peptide ligands; such signaling induces overt activation and causes the cells to proliferate. This scenario is consistent with the available data, but is largely hypothetical.
We and others have previously shown that efficient homeostatic proliferation requires TCR contact with self-MHC/peptide ligands that originally promoted positive selection of the T cells in the thymus (8, 9, 12). Since positive selection is a random process, mature T cells have a range of affinity, albeit small, for self-MHC/peptide ligands. Consequently, the question arises whether the variability in the strength of TCR affinity to self-MHC/peptide ligands can influence homeostasis of naive T cells. This question is also raised by the finding that certain lines of TCR-transgenic (TG) 4 T cells are incapable of undergoing homeostatic proliferation (8, 13).
To investigate the role of TCR affinity in homeostasis, we analyzed the homeostatic responses of three lines of TCR TG cells with different TCR affinities. The results indicate that the relative TCR affinity determines the homeostatic "fitness" of a particular T cell, including its ability to compete for factors that regulate cell survival and homeostatic proliferation. These findings suggest that in addition to IL-7 the relative affinity of the TCR to self-MHC/peptide ligands regulates homeostasis of naive T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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C57BL/6 (B6), B6.PL, and B6.CD45.1 mice were obtained from The Scripps Research Institute (TSRI) breeding colony. Sources of OT-I, 2C, anti-HY TCR TG and IL-7 TG mice were previously described (8, 14). OT-I.Thy-1.1 and 2C.CD45.1 mice were generated by mating OT-I and 2C mice with B6.PL and B6.CD45.1 mice, respectively.
Adoptive transfer and FACS analysis
Whole and CD8+ lymph node (LN) cells were prepared, CFSE labeled, and injected into irradiated or unirradiated hosts as described elsewhere (8). Donor B6.PL and OT-I.Thy-1.1 cells were detected using PE-conjugated anti-CD8 (eBioscience, San Diego, CA) and Cy5-conjugated anti-Thy-1.1 (eBioscience); donor 2C and HY cells were detected using PE-conjugated anti-CD8 and Cy5-conjugated anti-clonotypic 1B2 (eBioscience) and T3.70 (eBioscience), respectively. For surface marker expression, B6 and TCR TG cells were stained with FITC-conjugated anti-CD8 (eBioscience) plus Cy5-conjugated anti-Thy-1.1 or anti-clonotypic mAbs followed by PE-conjugated anti-TCR
, anti-CD5, anti-CD44, anti-CD122, or biotinylated-anti-IL-7R
(clone A7R34) followed by PE-conjugated streptavidin (Jackson ImmunoResearch Laboratories, West Grove, PA).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Although homeostatic proliferation in response to severe T depletion is readily observed with polyclonal T cells, studies with TCR TG mice indicate that some T cells are intrinsically incapable of undergoing homeostatic proliferation (Fig. 1). Thus, homeostatic proliferation is conspicuous for OT-I and 2C TCR TG T cells, but undetectable for others, as exemplified by the T3.70+ anti-HY clone (designated as HY; Fig. 1A and Ref13). For OT-I and 2C cells, it is notable that the rate of homeostatic proliferation is slightly faster for OT-I cells than for 2C cells (Fig. 1A). To investigate the reason behind this variability, the three lines of CD8+ TG cells were analyzed for expression of the receptors relevant for homeostatic proliferation, the TCR and IL-7R.
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chain-specific mAb H57-597, a hierarchy was apparent for TCR expression with the highest level on HY cells followed by 2C cells and then OT-I cells (Fig. 2A). IL-7R, by contrast, was expressed at comparable levels on the three clones (Fig. 2B). Despite the slight variability between the clones, the densities of TCR and IL-7R on TG cells were within the broad range expressed on polyclonal CD8+ cells (Fig. 2, A and B).
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CD5, which negatively regulates signaling through the TCR (15), has recently been shown to be expressed at a level directly proportional to the affinity of the TCR for self-MHC/peptide ligands encountered for thymic selection and peripheral cell survival (16, 17). Strikingly, the three clones varied significantly in their levels of CD5 expression, with the highest level on OT-I cells followed by 2C cells and then T3.70+ HY cells (Fig. 2C). Although CD5 levels on OT-I and 2C cells were within the range of density expressed by the bulk of polyclonal CD8+ cells, the median level of CD5 on T3.70+ HY cells was at the extreme low end of the spectrum expressed by polyclonal cells (Fig. 2C and Ref. 16).
For CD8+ T3.70+ HY cells, it should be mentioned that the low level of CD5 expression applied to TG cells from female mice, but not to TG cells from male mice. Thus, HY cells from male mice expressed high levels of CD5 comparable to those observed on T3.70- polyclonal CD8+ cells (Fig. 2D). Such a finding is consistent with the idea that the CD5 level increases with the rise in the strength of the signaling transmitted through the TCR from contact with self-ligands (16, 17). Interestingly, unlike female HY cells, male HY cells were capable of undergoing efficient homeostatic proliferation in irradiated female B6 hosts (Fig. 1B). However, the ability of male HY cells to undergo homeostatic proliferation did not appear to be a result of increased TCR affinity, but rather a consequence of conversion into memory-like cells. Thus, in contrast to T3.70+ cells from female HY mice, nearly all of the T3.70+ cells in male mice were found to be CD44high (data not shown and Ref. 18), and these cells underwent efficient homeostatic proliferation in irradiated female MHC class I-deficient hosts (Fig. 1B), presumably in response to cytokines (19).
Competition for homeostatic factors under lymphopenic conditions
The above findings with female HY cells indicate that the affinity of the TCR for self-ligands must be above a certain threshold for naive T cells to undergo homeostatic proliferation. Moreover, the finding that OT-I cells proliferated at a slightly faster rate than the lower affinity 2C cells suggests that TCR affinity may also influence the relative ability of naive T cells to undergo homeostatic proliferation. As discussed above, the signals from the TCR and IL-7R presumably synergize to mediate homeostatic proliferation. Accordingly, one could envisage that the strength of TCR affinity inversely regulates the amount of IL-7 required for naive cells to undergo homeostatic proliferation. If so, 2C cells could be more susceptible than OT-I cells to the effects of reduced availability of IL-7, i.e., under partly lymphopenic conditions.
To test the above idea, partly lymphopenic hosts were created by coinjecting a population of bystander T cells together with the CFSE-labeled 2C and OT-I cells into irradiated B6 hosts as previously described (8, 20). Bystander B6 CD8+ cells were injected at a dose (107/host) previously shown to be near the minimal numbers required for efficient inhibition of homeostatic proliferation (20). 2C and OT-I cells were mixed together with control B6 CD8+ cells, each expressing a combination of CD45 and Thy-1 congenic markers, so that the responses of all three types of cells can be directly compared. As previously shown (8, 20), coinjection of B6 bystander cells efficiently suppressed homeostatic proliferation of B6 CD8+ cells (Fig. 3, cf the top two rows). In the same hosts, proliferation of 2C cells was also severely suppressed, but strikingly, proliferation of OT-I cells was only moderately inhibited (Fig. 3). This finding is consistent with the notion that high-affinity T cells require less IL-7 than low-affinity cells to undergo homeostatic proliferation.
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The limited capacity of 2C bystander cells to suppress proliferation of B6 and OT-I cells is consistent with the recently reported finding (21, 22) that competition for specific self-MHC/peptide ligands is relevant for homeostatic proliferation. Nonetheless, the finding that OT-I bystander cells inhibited proliferation of B6 and 2C cells more efficiently than proliferation of autologous OT-I cells indicates that the relative ability to compete for specific ligands is also dependent on the affinity of the TCR. Thus, at least in terms of homeostatic proliferation, low-affinity cells (such as 2C) are ineffective at competing for specific self-ligands against high-affinity cells (such as OT-I), while high-affinity cells are efficient at competing against low-affinity cells.
Competition for specific MHC/peptide ligands under normal T-replete conditions
The above findings raise the question of whether competition for specific MHC/peptide ligands can influence homeostasis of naive T cells under normal T-sufficient conditions. To address this issue, a mixture of CFSE-labeled OT-I.Thy-1.1 and 2C.CD45.1 cells (5 x 106/each) was injected into unirradiated B6, OT-I and 2C hosts. The hosts were analyzed after a long incubation time (4 wk) because proliferation of naive T cells is very slow in unirradiated hosts. The total T cell counts in the three types of hosts were comparable (data not shown).
As shown in Fig. 4, CFSE-labeled OT-I cells did not proliferate in OT-I hosts, but underwent one to two rounds of cell division in B6 hosts and up to three rounds of cell division in 2C hosts. Likewise, the recoveries of OT-I cells tended to be slightly higher in B6 and 2C hosts than in OT-I hosts, presumably reflecting the differences in the rate of cell proliferation (Fig. 4A). This finding shows that OT-I cells do compete for specific MHC/peptide ligands, but the effect of this competition is apparent only under normal T-sufficient conditions.
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To examine competition among polyclonal T cells, a large number (107) of CFSE-labeled B6.CD45.1+ naive phenotype (CD44low) CD8+ cells were injected into unirradiated B6, OT-I, and 2C hosts and analyzed 4 wk later. Nearly all of the donor cells remained in interphase in B6 hosts, but a small fraction of the cells underwent either one or many rounds of cell division in OT-I and 2C hosts (Fig. 4A). The donor cell recoveries in the latter two hosts were also 
2-fold higher than those from B6 hosts (Fig. 4A).
Finally, to assess the role of specific MHC/peptide ligands under conditions of elevated levels of circulating IL-7, OT-I cells (107) were injected into B6, OT-I, and 2C hosts bred to an IL-7 TG background. The total T cell counts in these three IL-7 TG hosts were similar and were 10-fold above T cell counts in normal B6 mice (Ref. 14 and data not shown). Significantly, the ability of OT-I cells to proliferate and persist in greater numbers in B6 and 2C hosts, in comparison to OT-I hosts, was more pronounced in IL-7 TG hosts (Fig. 4B). Thus, while donor OT-I cells remained mostly in interphase in OT-I.IL-7 TG hosts, OT-I cells underwent one to three rounds of cell division in B6.IL-7 TG hosts and two or more rounds of cell division in 2C.IL-7 TG hosts, with corresponding increases in cell recoveries (Fig. 4B).
Collectively, these findings strongly suggest that clonal competition for specific MHC-peptide complexes plays an important role in regulating homeostasis of naive T cells even under normal T-sufficient conditions. Results from the two TCR TG donor cells illustrate that the outcome of such regulation depends on the strength of TCR affinity. If the behavior of the two clones are representative of normal T cells, the data thus suggest that T cells with relative high affinity for self-ligands have a survival advantage over low-affinity T cells. This idea is consistent with the finding that T3.70+ HY cell numbers decline rapidly in thymectomized HY TG mice, presumably due to competition from polyclonal cells expressing endogenous TCR (13). The above data furthermore suggest that the advantage of high-affinity cells may induce high-affinity cells to undergo slow cell division in response to self-ligands, whereas low-affinity cells survive without undergoing cell division. Moreover, the data suggest that survival and proliferation induced by TCR contact with self-ligands are regulated by IL-7. This idea is supported by the finding that background proliferation of OT-I cells to self-ligands was dramatically enhanced in IL-7 TG hosts. In essence, the relative responsiveness to IL-7 appears to be regulated by the amount of TCR signaling, which in turn is dictated by the affinity of the receptor and the availability of the specific self-ligands.
In terms of total cell recoveries, it is of interest that the survival of 2C cells in autologous 2C hosts was no lower than in OT-I hosts. These findings suggest that competition for self-ligands is less important for survival in interphase than for homeostatic proliferation. In this respect, it should be noted that, in contrast to OT-I cells, proliferation of 2C cells in unirradiated hosts was virtually undetectable.
The failure of polyclonal B6 cells to proliferate in B6 hosts suggests that competition between polyclonal cells is especially pronounced, presumably due to the absence of any obvious "holes" in the repertoire. In addition, it is surprising that a small subset of these B6 cells proliferated rapidly in unirradiated OT-I and 2C hosts, although not in autologous B6 hosts; similar data have been reported by other workers (22). Although it is possible that such proliferation represents high-affinity cells responding to self-ligands (22), we believe this to be unlikely considering the slow proliferation of OT-I cells in 2C hosts. A more likely explanation for this finding is that, being immunodeficient, TCR TG mice have a higher baseline level of infection than normal mice. According to this idea, the small subset of rapidly dividing cells in these hosts is expanding in response to exogenous rather than endogenous Ags. This possibility is being assessed.
In summary, the findings in this report collectively suggest that the relative homeostatic fitness of a naive T cell is influenced by the affinity of the TCR for self-MHC/peptide ligands, whereby high-affinity cells have a survival advantage over low-affinity cells. The current work is also consistent with a recent report showing that the avidity for MHC/peptide ligands similarly controls homeostasis of naive CD4 cells (23). Mechanistically, the survival advantage of high-affinity cells appears to be a result of enhanced responsiveness to IL-7 and increased competitiveness for specific self-MHC/peptide ligands. The TCR-affinity-controlled clonal competition probably shapes the repertoire of the naive T cell pool in normal mice, even though a wide distribution of CD5 expression on polyclonal cells suggests that the effect may be subtle. Lack of enrichment of high-affinity cells (CD5high) may be due to continuous thymic output in young individuals; therefore, whether such skewing is evident after thymectomy or with aging is currently under investigation. One condition where preferential expansion of high-affinity cells is expected to occur is during homeostatic proliferation. Thus, populations of polyclonal T cells that have undergone many rounds of homeostatic proliferation do express a slightly higher level of CD5 than normal T cells (data not shown). This mode of enrichment for high-affinity cells presumably contributed to the enhanced responses against tumor-associated self-Ags when the tumor-bearing hosts were rendered lymphopenic before the T cell therapy (24, 25). In addition, it is possible that homeostasis-driven expansion of cells with high affinity to self-Ags contributes to increased incidence of autoimmunity observed under partially lymphopenic conditions (26, 27).
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
3 Address correspondence and reprint requests to Dr. Charles D. Surh, Department of Immunology, IMM-26, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: csurh{at}scripps.edu
4 Abbreviations used in this paper: TG, transgenic; LN, lymph node.
Received for publication September 9, 2003. Accepted for publication October 14, 2003.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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