Interleukin-7 Produced by Antigen Presenting Cells Regulates the Homeostatic Peripheral Expansion of Naive CD4 T Cells.

Interleukin-7 (IL-7) is the only cytokine demonstrated thus far to directly support the development and maintenance of naive T cells. Interleukin-7 is produced mainly by the stroma of lymphoid organs but also to a lesser extent by antigen presenting cells. Dynamic changes in the relative availability of IL-7 during lymphopenia support T cell homeostatic peripheral expansion (HPE). Whereas HPE is very efficient at reconstituting the pool of mature CD8 T lymphocytes, regeneration of CD4 T lymphocytes via HPE is more problematic and deficits in CD4 T lymphocytes persist for years in humans following lymphodepletion. We demonstrate that in mice, CD4+ T cells undergo substantially diminished HPE compared to CD8+ T cells during lymphopenia. We hypothesized that CD4+ T cells uniquely require both MHC Class II plus IL-7 for survival and expansion during lymphopenia and that the availability of these signals are limited by the availability of IL-7 producing APCs. Consistent with this hypothesis, studies performed in chimeric mice showed that cells derived from APCs, but not stromal cells, provided the endogenous IL-7 that is require for naive CD4+ T cell HPE. Furthermore, whereas systemic exposure to high levels of rhIL-7 did not induce efficient homeostatic peripheral expansion of CD4+ cells, in vivo modulation of Class II expressing cells by flt3 ligand promoted homeostatic expansion of CD4+ T cells. Surprisingly however, we found that APCs respond to elevated systemic IL-7 by diminishing production of IL-7, a loop mediated by IL-7Rα and Stat5. As a result, elevated systemic IL-7 levels present during lymphopenia paradoxically diminish the production of IL-7 by APCs and thereby diminish CD4 HPE. This was directly demonstrated by experiments wherein CD4+ HPE was dramatically augmented in chimeric mice generated such that bone marrow derived cells lacked IL7Rα or Stat5. This work demonstrates a critical role for APC derived IL-7 in CD4+ regeneration and provides a new paradigm for understanding why prolonged CD4+ lymphopenia occurs following T cell depletion in humans.