Investigation of the role of the common gamma chain in early T cell development in a canine model of X -linked severe combined immunodeficiency

T cell development is a coordinated process regulated by, among other things, signaling via cytokines and their receptors. Any given step in this development may be regulated by more than one cytokine and, conversely, any given cytokine may mediate several developmental steps. Cytokines, which signal via receptors having the common gamma chain (γc) as an integral component, participate in the regulation of T cell development in this manner. X-linked severe combined immunodeficiency (XSCID), a genetic disease resulting from mutations in the gene for the common gamma chain, is characterized, in part, by defective T cell development. Dogs with XSCID have been shown to have a partial block in thymocyte development at the double negative (DN; CD4−CD8−) to double positive (DP; CD4+CD8+) transition. Determination of the timing of, and the critical mechanisms responsible for, this block should allow an understanding of the normal role of γc-dependent signaling in thymocyte development. To identify the stage at which regulation of development of intrathymic T cells via γc-dependent signaling first occurs, X-inactivation patterns were examined in subsets of thymic cells from XSCID carrier females. The role of the γc in early thymocyte development was explored by examination and comparison of thymi from XSCID and age-matched normal dogs. Finally, to determine if environmental antigens have a role in γc-dependent and γc-independent thymocyte development, thymi from gnotobiotic normal and XSCID dogs were examined and compared with their conventionally-reared counterparts. Analysis of the results indicate that γc-dependent signaling is functionally necessary for development of the DN subset of thymocytes thus supporting a role for γc-mediated signaling in the proliferation and survival of thymic lymphocytes at the DN stage. The role of γc-dependent signaling was shown to change with age. Additionally, environmental antigens were shown to play a part in γc-independent pathways of thymocyte development. In conclusion, in the dog, signaling via γc-dependent receptors has been demonstrated to coordinately regulate the development of DN thymocytes in a thymocyte stage-specific and animal age-specific manner yielding a model for the role of the γcc that differs from the accepted murine model