Critical role for the common cytokine receptor γ chain in intrathymic and peripheral T cell selection

Abstract

The common cytokine receptor γ chain (γ), which is a functional subunit of the receptors for interleukins (IL)-2, -4, -7, -9, and -15, plays an important role in lymphoid development. Inactivation of this molecule in mice leads to abnormal T cell lymphopoiesis characterized by thymic hypoplasia and reduced numbers of peripheral T cells. To determine whether T cell development in the absence of γ(c) is associated with alterations of intrathymic and peripheral T cell selection, we have analyzed γ(c)-deficient mice made transgenic for the male-specific T cell receptor (TCR) HY (HY/γ(c) mice). In HY/γ(c) male mice, negative selection of autoreactive thymocytes was not diminished; however, peripheral T cells expressing transgenic TCR-α and -β chains (TCR-α(T)/β(T)) were absent, and extrathymic T cell development was completely abrogated. In HY/γ(c) female mice, the expression of the transgenic TCR partially reversed the profound thymic hypoplasia observed in nontransgenic γ(c) mice, generating increased numbers of thymocytes of all subsets, particularly the TCR-α(T)/β(T) CD8+ single- positive thymocytes. Despite efficient positive selection, however, naive CD8+ TCR-α(T)/β(T) T cells were severely reduced in the peripheral lymphoid organs of HY/γ(c) female mice. These results not only underscore the indispensable role of γ(c) in thymocyte development, but also demonstrate the critical role of γ, in the maintenance and/or expansion of peripheral T cell pools.