Interleukin-7 restores immunity in athymic T-cell–depleted hosts

Abstract

Thymic-deficient hosts rely primarily on antigen-driven expansion to restore the peripheral T-cell compartment following T-cell depletion (TCD). The degree to which this thymic-independent pathway can restore immune competence remains poorly understood but has important implications for a number of clinical conditions including stem cell transplantation and human immunodeficiency virus (HIV) infection. A model of HY-mediated skin graft rejection by athymic, TCD mice was used to show that restoration of naive and recall responses via peripheral expansion requires transfer of only 25 ؋ 10 6 lymph node (LN) cells representing approximately 10% of the T-cell repertoire. Consitutive expression of bcl-2 in the expanding inocula restored recall responses to HY at a substantially lower LN cell dose (1 ؋ 10 6 ), which is normally insufficient to induce HY-mediated graft rejection in athymic hosts. Interestingly, bcl-2 had no effect on primary responses. Interleukin-7 (IL-7) potently enhanced thymic-independent peripheral expansion and led to HY graft rejection using an LN cell dose of 1 ؋ 10 6 in both primary and recall models. The restoration of immune competence by IL-7 appeared to be mediated through a combination of programmed cell death inhibition, improved costimulation, and modulation of antigenpresenting cell (APC) function. These results show that immune competence for even stringent antigens such as HY can be restored in the absence of thymic function and identify IL-7 as a potent modulator of thymic-independent T-cell regeneration. ( IntroductionAcute depletion of the T-cell compartment occurs in a number of clinical situations including stem cell transplantation, human immunodeficiency virus (HIV) infection, and after intensive cytotoxic therapy for cancer. Restoration of immune competence following T-cell depletion (TCD) requires the regeneration of a functionally intact, diverse T-cell pool that is capable of responding to foreign antigens and, potentially, altered self-antigens expressed by tumors. Previous studies have shown that there are 2 main pathways capable of substantial peripheral T-cell regeneration: thymic-dependent regeneration from bone marrow progenitors and thymic-independent peripheral expansion of mature T-cell populations. 1 The relative contribution of these 2 pathways is dynamic and dependent on the degree of thymic function. Current concepts hold that the capacity of the host to restore immune competence depends primarily on the extent to which thymic pathways contribute to T-cell regeneration. However, due to disease, therapy-related toxicity, and age-related changes, thymic function is frequently limiting, resulting in a relative reliance on thymic-independent peripheral expansion in many clinical situations associated with TCD. [2][3][4][5][6][7][8] The degree to which the peripheral expansion of mature T-cell populations can restore host immune competence following TCD remains poorly understood and is the focus of this report.Peripheral expansion is predicted to give rise to limit...

Positive Effects of Glucocorticoids on T Cell Function by Up-Regulation of IL-7 Receptor α

“…Also, T cell homeostasis is mediated by signals transmitted by growth factor receptors in secondary lymphoid and in nonlymphoid organs (3,49,53,54). IL-7 potently enhances thymic-independent peripheral expansion and restores immunity in athymic T cell-depleted hosts (55). Furthermore, IL-7 is required for homeostatic expansion of naive CD8 ϩ and CD4 ϩ T cells in lymphopenic hosts and is partially required for the homeostatic proliferation of memory cells (22).…”

“…Furthermore, IL-7 is required for homeostatic expansion of naive CD8 ϩ and CD4 ϩ T cells in lymphopenic hosts and is partially required for the homeostatic proliferation of memory cells (22). These two studies point to IL-7 as an important cytokine in T cell homeostasis (22,55). Therefore, improved IL-7R␣ signaling by glucocorticoids may contribute to IL-7-mediated expansion of memory T cells and maintenance of the peripheral T cell repertoire (56 -58).…”

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

“…In contrast, IL-7 availability is increased during primary HIV-1 infection and persists, likely as a response to or as a cause of lymphopenia. Indeed, IL-7 levels are inversely correlated with CD4 ϩ T cell counts (33)(34)(35)(36).…”

Interleukin-7 and Immunorestoration in HIV: Beyond the Thymus

“…However, given the degree to which thymic function may be limited in clinical situations associated with T cell depletion, an important question is the extent to which the ability for IL-7 to enhance peripheral expansion can restore immune competence. Indeed, in a murine model assessing responses to a stringent antigen following T cell depletion of athymic mice, we have demonstrated that the administration of IL-7 can potently modulate functional immune responses (22). Thus, even in the complete absence of thymic function, potent effects of IL-7 in the periphery can lead to functional immune competence, thus improving the function of an otherwise limited repertoire.…”

“…One clear effect of IL-7 on mature peripheral T cells is the inhibition of programmed cell death, which is present at high levels in patients with T cell depletion (22)(23)(24). IL-FRY AND MACKALL 804 FIG.…”