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• W1482775574 abstract "Maintenance of T cells is critical for sustained readiness against infectious challenges. Naïve CD8 T-cell homeostasis requires at least two signals: T-cell receptor (TCR) contact with self-peptide/major histocompatibility complex (self-pMHC) and interleukin (IL)-7 engagement with IL-7 receptor (IL-7R).1,2 However, the mechanisms by which these signals influence maintenance of a diverse naïve T-cell pool are still unclear. The study by Palmer et al.3 in this issue introduces a new perspective on T-cell homeostasis by demonstrating how subtle heterogeneity in IL-7R expression dictates maintenance of distinct populations within the naïve CD8 T-cell pool. Analyzing both TCR transgenic and polyclonal T cells, the authors show that the ability to respond to IL-7 signals differs dramatically for distinct naïve CD8 T-cell populations. The cell-surface protein CD5 proved to be a useful marker, with CD5high cells being more responsive to IL-7 than CD5low cells. Whether CD5 is functionally relevant to these differences is debatable, however, as further work by Palmer et al. argue that a subtle increase in IL-7Rα expression levels, rather than changes in intrinsic IL-7R signaling capacity, was the basis for enhanced reactivity of CD5high T cells. A consequence of this heterogeneity was a profound difference in the impact of IL-7 exposure levels, with high IL-7 concentrations inducing proliferation of CD5high (but not CD5low) cells, whereas CD5low cells exhibit enhanced survival after IL-7 deprivation. Earlier studies indicated that naïve CD8 T-cell homeostasis is controlled by an active “tuning” process, mediated by cross-talk between TCR and IL-7R signals.4,5 Hence, heterogeneity in IL-7Rα expression could reflect a dynamic extrinsic process, driven by the “strength” of TCR signaling. Palmer et al. address this by testing whether sensitivity to IL-7 is influenced by simultaneous TCR/self-pMHC interactions or whether IL-7 reactivity has become ‘programed’ into distinct naïve CD8 T-cell pools. Importantly, they show that CD5high and CD5low naïve T-cell pools maintain distinct capacities to respond to IL-7 in the absence of ongoing TCR/self-pMHC stimulation, suggesting that these differences are at least somewhat stable. These findings echo another report, which also examined the cytokine sensitivity of CD5high and CD5low naïve CD8 T cells, but with some important differences. In their study, Cho et al.6 focused on responses to IL-2 and IL-15, both of which signal through the IL-2/15Rβ chain (CD122). Like Palmer et al., these authors concluded that CD5high T cells had increased cytokine sensitivity, manifested as a robust response to IL-2 and IL-15. However, these authors proposed that the enhanced response did not depend on altered cytokine receptor expression but rather on recruitment of CD122 to lipid rafts, allowing enhanced signaling through the IL-2 and IL-15 receptors. In contrast, Palmer et al. take pain to show that the “quality” of the signals induced by IL-7R are similar for CD5low and CD5high T cells, suggesting that modest changes in IL-7Rα levels determine the threshold for cytokine reactivity. Whether these data suggest sensitivity to distinct homeostatic cytokines operating through different mechanisms is not yet clear. Intrinsic differences in T-cell sensitivity to IL-7 implies that a subset of IL-7Rαhigh naïve T cells could outcompete their peers with lower IL-7Rα expression and drastically decrease TCR diversity within the T-cell pool. As proof of principle, mice were continuously delivered IL-7 via osmotic pumps: CD5high T cells were found to have preferentially proliferated, leading to a skewing of the CD8 T-cell pool. In normal animals (and, in vitro, with submitogenic doses of IL-7), survival of both CD5high and CD5low cells is similar; hence, both populations could be maintained in balance if such IL-7 levels are never exceeded. Still, it seems surprising that, over the long-term, the CD5low pool does not succumb to the superior homeostatic potential of their CD5hi counterparts. However, further analysis by Palmer et al. may provide an answer for this paradox. Although all naïve CD8 T cells need IL-7 to survive, the authors show that the CD5low pool is maintained better than the CD5high population when IL-7 is limiting or absent. Furthermore, both the basal and IL-7-induced levels of glucose transport in CD5low cells exceed that of the CD5high pool. Such findings argue that different conditions might favor maintenance of distinct pools, with progeny of CD5high cells enriched when available IL-7 is abundant (as, for example, in situations of T-cell lymphopenia), whereas low accessible IL-7 levels (as when the T-cell compartment is overfull) may provide a survival edge for the CD5low pool (Figure 1). Another conclusion from such a model is that although the CD5high population waxes and wanes depending on changes in available IL-7 levels, the CD5low pool may be more stable over the long-term. Although the report by Palmer et al. adds to the evidence that naïve T cells are intrinsically programed for their homeostatic potential, the underlying mechanism for such programing is not clear. Although simultaneous TCR engagement with self-pMHC may not be required for IL-7 responsiveness studied by the authors, considerable data suggest that efficient TCR engagement during development and/or long-term maintenance drive increased levels of CD5 and IL-7Rα. Such findings prompt the question of why T cells with a stronger TCR/self-pMHC interaction should be favored for proliferative reactivity toward homeostatic cytokines—especially as this would appear to favor potentially autoreactive cells. Furthermore, as shown by Palmer et al. and by others,6 heterogeneity in CD5 expression and sensitivity to γc-cytokines can also be detected among monoclonal TCR transgenic CD8 T-cell populations, suggesting that there are differences in T-cell development or maintenance independently of TCR specificity for self-pMHC. This leads to a larger issue—although diversity among naïve CD8 T cells as studied by Palmer et al. suggests differential homeostatic potential, what impact does this have on the naïve CD8 T-cell response to a foreign antigen? In vitro studies by Cho et al.6 suggested altered cytokine reactivity by CD5high naïve CD8 T cells may make them more responsive to CD4 T-cell help—whether naïve CD8 T-cell heterogeneity influences in vivo responses will need to be addressed. Subtle differences in IL-7R expression by naïve CD8 T cells influence their homeostasis. Analysis of heterogeneity within the naïve CD8 T-cell pool demonstrates a population with elevated expression levels of CD5 and IL-7Rα. The modest elevation in IL-7Rα levels results in enhanced sensitivity to IL-7 by the CD5high cells, and has important consequences for naïve CD8 T-cell homeostasis. Under normal conditions, the levels of IL-7 permit survival of both CD5low and CD5high CD8 T cells; however, when available IL-7 is abundant (for example, in conditions of T-cell lymphopenia), naïve CD8 T cells within the CD5high pool proliferate and can become dominant. On the other hand, under conditions of limiting IL-7, the survival of CD5low cells is favored, likely related to their higher basal level of glucose intake compared with the CD5high pool." @default.
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• W1482775574 date "2011-04-12" @default.
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• W1482775574 title "Not all naïve CD8 T cells are created equal" @default.
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• W1482775574 doi "https://doi.org/10.1038/icb.2011.27" @default.
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