Trends in Immunology
ReviewInterleukin-7: master regulator of peripheral T-cell homeostasis?
Section snippets
IL-7: background and biology
IL-7 has been shown unequivocally to be a requisite cytokine for lymphopoiesis, because animals deficient in IL-7 are essentially devoid of B- and T-cells 12, 13, 14, 15. Clinical studies of patients with congenital immunodeficiencies have confirmed a requirement for IL-7 for primary T-cell development in humans; however, IL-7 is not required for the development of B cells in humans 16. Because of the profound effects of IL-7 on developing lymphocytes, it is not surprising that these effects
Peripheral homeostatic expansion in TCD hosts
The adoptive transfer of mature T cells into T-cell-replete mice does not induce a sufficiently chimeric state to study the biology of the transferred cells. To facilitate the ‘take’ of the adoptively transferred T cells, it is common practice to use TCD hosts, in essence, to provide ‘space’ for the transferred T cells 3, 4, 5. The expansion of mature T-cell populations in TCD hosts has been variably termed ‘peripheral expansion’ or ‘peripheral homeostatic expansion’ (PHE). This expansion is
IL-7 is a crucial cytokine during peripheral homeostatic expansion
The administration of IL-7 increases the rate of T-cell immune reconstitution following bone-marrow transplantation and/or cytotoxic chemotherapy in mice 40, 41, 42. Because IL-7 has potent effects on developing thymocytes as well as peripheral T cells, experiments were undertaken to distinguish the ability of IL-7 to modulate thymopoiesis from its effects on the expansion of peripheral T-cell populations. IL-7 increased substantially both thymic-dependent T-cell regeneration and the peripheral
Elevations in the level of IL-7 in clinical settings associated with T-cell depletion
The identification of IL-7 as a requisite factor for homeostatic expansion in response to low-affinity Ags provided clear evidence that at least a basal level of constitutive IL-7 is required for PHE to occur. However, the observations that exogenous IL-7 could potently enhance PHE in TCD hosts and induce PHE in T-cell-replete hosts raised the possibility that changes in endogenous levels of IL-7 might be responsible for modulating the differential rates of PHE observed in TCD versus
CD8+ expansions following CD4+ depletion: insights into ‘blind homeostasis’?
Clinical and murine studies have shown that the isolated depletion of CD4+ T cells leads to the expansion of CD8+ T-cell populations 50, 51, 52. This observation has led to the ‘blind homeostasis’ model of T-cell regulation, which holds that the immune system will respond to the depletion of T-cell subsets by expanding whatever population remains available. Invoking IL-7 as a master regulator of T-cell homeostasis could account for these observations, because isolated subset depletion, at least
Conclusions
IL-7 is well recognized as a crucial cytokine for the early development of lymphocytes. Recent work has illustrated that IL-7 modulates potently peripheral T-cell responses to cognate Ag in vivo 22 and that IL-7 is a nonredundant cytokine for the PHE that occurs in TCD hosts 6, 7. Furthermore, clinical studies of TCD humans show that circulating levels of IL-7 are elevated in response to T-cell depletion and return to normal upon recovery of T-cell populations 9, 10, 11. Together, these data
Acknowledgements
We would like to thank Ronald E. Gress for careful review of this manuscript and helpful discussions.
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