Homeostatic signals that control the overall size and composition of the naive T cell pool have recently been identified to arise from contact with self-MHC/peptide ligands and a cytokine, IL-7. IL-7 presumably serves as a survival factor to keep a finite number of naive cells alive by preventing the onset of apoptosis, but how TCR signaling from contact with self-MHC/peptide ligands regulates homeostasis is unknown. To address this issue, murine polyclonal and TCR-transgenic CD8+ cells expressing TCR with different affinities for self-MHC/peptide ligands, as depicted by the CD5 expression level, were analyzed for their ability to respond to and compete for homeostatic factors under normal and lymphopenic conditions. The results suggest that the strength of the TCR affinity determines the relative “fitness” of naive T cells to compete for factors that support cell survival and homeostatic proliferation.

Following selection against self-MHC/peptide ligands, mature T cells exit the thymus, join the peripheral T cell pool, and become subject to regulation by homeostatic mechanisms (1, 2). The overall size and composition of the naive and memory T cell populations are thought to be controlled independently by different mechanisms (3). Recent work has shown that naive T cell homeostasis is largely controlled by signals from contact with two ligands, self-MHC/peptide complexes and the cytokine IL-7 (4, 5). The importance of these two factors is manifested by the finding that lack of contact with either of these two ligands considerably shortens the life span of naive T cells and abrogates the ability of these cells to undergo efficient “homeostatic” proliferation in response to severe T cell depletion (6, 7, 8, 9, 10, 11).

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.

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.

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-TCRβ, anti-CD5, anti-CD44, anti-CD122, or biotinylated-anti-IL-7Rα (clone A7R34) followed by PE-conjugated streptavidin (Jackson ImmunoResearch Laboratories, West Grove, PA).

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. 1,A 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. 1 A). 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.

FIGURE 1.

Variability in naive T cells to undergo homeostatic proliferation. A, Not all clones can undergo homeostatic proliferation. Small numbers (2 × 106/mouse) of CFSE-labeled LN cells from the indicated donor mice were injected into irradiated (600 cGy) B6 mice and the donor cells in host LN were analyzed 8 days later. Shown are CFSE profiles of donor CD8+ cells detected by double staining for CD8 and Thy-1.1 for B6 and OT-I cells bred to a Thy-1.1+ background, and for CD8 and clonotypic TCR using mAbs 1B2 and T3.70, and for 2C and HY cells, respectively. B, Homeostatic proliferation of HY cells from male mice. Small numbers of CFSE-labeled purified CD8+ cells from HY male mice were injected into the indicated hosts and the donor cells were analyzed 7 days later as described in A.

FIGURE 1.

Variability in naive T cells to undergo homeostatic proliferation. A, Not all clones can undergo homeostatic proliferation. Small numbers (2 × 106/mouse) of CFSE-labeled LN cells from the indicated donor mice were injected into irradiated (600 cGy) B6 mice and the donor cells in host LN were analyzed 8 days later. Shown are CFSE profiles of donor CD8+ cells detected by double staining for CD8 and Thy-1.1 for B6 and OT-I cells bred to a Thy-1.1+ background, and for CD8 and clonotypic TCR using mAbs 1B2 and T3.70, and for 2C and HY cells, respectively. B, Homeostatic proliferation of HY cells from male mice. Small numbers of CFSE-labeled purified CD8+ cells from HY male mice were injected into the indicated hosts and the donor cells were analyzed 7 days later as described in A.

Close modal

Interestingly, as shown by staining with the TCRβ 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. 2,A). IL-7Rα, by contrast, was expressed at comparable levels on the three clones (Fig. 2,B). Despite the slight variability between the clones, the densities of TCRβ and IL-7Rα on TG cells were within the broad range expressed on polyclonal CD8+ cells (Fig. 2, A and B).

FIGURE 2.

Expression of TCRβ, IL-7R, and CD5 on B6, OT-I, 2C, and HY CD8+ cells. LN CD8+ cells from the indicated 4- to 6-wk-old mice were stained for expression of TCRβ (A), IL-7Rα (B), and CD5 (C and D). Since RAG+ TCR TG mice were used for staining, cells were stained with the following markers, in addition to CD8, to ensure analysis of only TG cells: TCR Vα2 for OT-I cells, clonotypic TCR detected by mAb 1B2 for 2C cells, and clonotypic TCR detected by mAb T3.70 for HY cells. T3.70CD8+ cells from female HY mice were used as nonclonotypic cells.

FIGURE 2.

Expression of TCRβ, IL-7R, and CD5 on B6, OT-I, 2C, and HY CD8+ cells. LN CD8+ cells from the indicated 4- to 6-wk-old mice were stained for expression of TCRβ (A), IL-7Rα (B), and CD5 (C and D). Since RAG+ TCR TG mice were used for staining, cells were stained with the following markers, in addition to CD8, to ensure analysis of only TG cells: TCR Vα2 for OT-I cells, clonotypic TCR detected by mAb 1B2 for 2C cells, and clonotypic TCR detected by mAb T3.70 for HY cells. T3.70CD8+ cells from female HY mice were used as nonclonotypic cells.

Close modal

For polyclonal T cells, TCR affinity for self-MHC/peptide ligands is presumed to vary, ranging from low to moderate. Since the density of the TCR may influence the overall strength of the TCR signaling, it is possible that the TCR level on naive T cells is established and maintained in a manner inversely proportional to its affinity for the self-MHC/peptide ligands. Such a mechanism may ensure that the overall intensity of the signaling through the TCR from contact with self-MHC/peptide ligands is strong enough to deliver survival signals without activating the T cells. According to this idea, the affinity of the TCR for self-ligands is highest for OT-I cells followed by 2C cells and then HY cells. To test the validity of this idea, the three clones were analyzed for the expression of CD5.

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. 2,C). 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. 2 C 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. 2,D). 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. 1,B). 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. 1 B), presumably in response to cytokines (19).

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.

FIGURE 3.

OT-I and 2C TG cells differ in their competitiveness for homeostatic factors in lymphopenic hosts. A mixture of CFSE-labeled purified B6.Thy-1.1.CD45.1, 2C.CD45.1, and OT-I.Thy-1.1 CD8+ cells (2 × 106/ea) was injected into a group of irradiated (600 cGy) B6 mice. Some of the hosts also received 1 × 107 B6, 2C, or OT-I CD8+ purified cells. The CFSE profiles of donor cells were analyzed 7 days later by staining host LN and spleen cells for CD8, CD45.1, and Thy-1.1. Shown are data from LN.

FIGURE 3.

OT-I and 2C TG cells differ in their competitiveness for homeostatic factors in lymphopenic hosts. A mixture of CFSE-labeled purified B6.Thy-1.1.CD45.1, 2C.CD45.1, and OT-I.Thy-1.1 CD8+ cells (2 × 106/ea) was injected into a group of irradiated (600 cGy) B6 mice. Some of the hosts also received 1 × 107 B6, 2C, or OT-I CD8+ purified cells. The CFSE profiles of donor cells were analyzed 7 days later by staining host LN and spleen cells for CD8, CD45.1, and Thy-1.1. Shown are data from LN.

Close modal

The overall intensity of TCR signaling is determined partly by TCR affinity for MHC/peptide ligand, but also by ligand density. It is thus possible that competition between T cells for specific self-MHC/peptide ligands may influence the ligand availability and thereby the ability of naive T cells to undergo homeostatic proliferation. To test this idea, OT-I and 2C cells were used as bystander cells. The rationale here was that TCR TG cells with restricted specificity would suppress homeostatic proliferation of autologous cells more severely than cells with unrelated specificity. At a low dose of bystander cells (107/host), 2C bystander cells suppressed proliferation of autologous 2C cells more effectively than proliferation of B6 CD8+ cells or OT-I cells (Fig. 3, third row). In contrast, inhibition of proliferation by OT-I bystander cells was less prominent for OT-I cells than for B6 or 2C cells (Fig. 3, fourth row). Preferential inhibition of OT-I cell proliferation by OT-I bystander cells became prominent with a higher dose of bystander cells (see Competition for specific MHC/peptide ligands under normal T-replete conditions).

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.

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 × 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. 4 A). 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.

FIGURE 4.

Competition for homeostatic factors in T-replete conditions. A, Competition in IL-7 wild-type hosts. A mixture of CFSE-labeled purified OT-I.Thy-1.1 and 2C.CD45.1 CD8+ cells (5 × 106/each) was coinjected into unirradiated B6, OT-I, and 2C mice. The CFSE profile of donor cells was analyzed 4 wk later by staining host LN and spleen cells for Thy-1.1 and CD45.1. A separate group of mice was also injected with CFSE-labeled purified B6.PL CD44lowCD8+ cells (107/each) and analyzed 4 wk later by staining for CD8 and Thy-1.1. Histograms of donor cells are shown from LN. Total numbers of donor cells recovered from host LN and spleens are also shown. B, Competition in IL-7 TG hosts. CFSE-labeled purified OT-I.Thy-1.1 cells (107/each) were injected into unirradiated B6.IL-7 TG, OT-I.IL-7 TG, and 2C.IL-7 TG mice and analyzed 4 wk later as describe in A.

FIGURE 4.

Competition for homeostatic factors in T-replete conditions. A, Competition in IL-7 wild-type hosts. A mixture of CFSE-labeled purified OT-I.Thy-1.1 and 2C.CD45.1 CD8+ cells (5 × 106/each) was coinjected into unirradiated B6, OT-I, and 2C mice. The CFSE profile of donor cells was analyzed 4 wk later by staining host LN and spleen cells for Thy-1.1 and CD45.1. A separate group of mice was also injected with CFSE-labeled purified B6.PL CD44lowCD8+ cells (107/each) and analyzed 4 wk later by staining for CD8 and Thy-1.1. Histograms of donor cells are shown from LN. Total numbers of donor cells recovered from host LN and spleens are also shown. B, Competition in IL-7 TG hosts. CFSE-labeled purified OT-I.Thy-1.1 cells (107/each) were injected into unirradiated B6.IL-7 TG, OT-I.IL-7 TG, and 2C.IL-7 TG mice and analyzed 4 wk later as describe in A.

Close modal

Unlike OT-I cells, most donor 2C cells remained in interphase during the 4-wk period in B6, OT-I, and 2C hosts (Fig. 4,A). Nevertheless, the recoveries of 2C cells from OT-I and 2C hosts were 3- to 4-fold greater than those from B6 hosts (Fig. 4 A). Although the recoveries of 2C and OT-I cells from TCR TG hosts were comparable, there was a considerable disparity from B6 hosts. Thus, the recoveries of OT-I cells from B6 hosts were consistently 3- to 4-fold greater than the recoveries of 2C cells from B6 hosts. This difference was observed even at earlier time points before any proliferation by OT-I cells (data not shown), indicating that OT-I cells are inherently better than 2C cells in competing for survival factors against polyclonal B6 cells.

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. 4,A). The donor cell recoveries in the latter two hosts were also ∼2-fold higher than those from B6 hosts (Fig. 4 A).

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. 4,B). 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. 4 B).

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).

We thank Dr. Jon Sprent for critically reading this manuscript and K. Ayala, J. Kuhns, and D. Kim for various supports. This is publication number 15536-IMM from TSRI.

1

This work was supported by U.S. Public Health Service Grants AI41079, AI45809, and AG20186 (to C.D.S.). W.C.K. was supported by U.S. Public Health Service Institute National Research Service Award AI07244. C.D.S. is a Scholar of the Leukemia and Lymphoma Society.

4

Abbreviations used in this paper: TG, transgenic; LN, lymph node.

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