Phenotypic and functional analysis of positive selection in the γ/δ T cell lineage

Recent evidence suggests that T cells expressing γ/δ antigen receptors (T cell receptor [TCR]) are subject to positive selection during development. We have shown that T cells expressing a class I major histocompatibility complex (MHC)-specific γ/δ TCR transgene (tg) are not positively selected in class I MHC-deficient, β₂-microglobulin (β₂m) gene knockout mice (tg⁺ β₂m^-). In this report, we examine phenotypic and functional parameters of γ/δ positive selection in this transgenic model system. TCR-γ/δ tg⁺ thymocytes of mature surface phenotype (heat stable antigen^-, CD5^hi) were found in β₂m^- but not in β₂m^- mice. Moreover, subsets of tg⁺ thymocytes with the phenotype of activated T cells (interleukin [IL]2R⁺, CD44^hi, or Mel-14lo) were also present only in the β₂m⁺ mice. Cyclosporine A, which blocks positive selection of TCR-α/β T cells, also inhibited γ/δ tg⁺ T cell development. These results support the idea that positive selection of TCR-γ/δ requires active TCR-mediated signal transduction. Whereas tg⁺ β₂m⁺ thymocytes produced IL-2 and proliferated when stimulated by alloantigen, TCR engagement of tg⁺ β₂m^- thymocytes by antigen induced IL-2R expression but was uncoupled from the signal transduction pathway leading to IL-2 production and autocrine proliferation. Overall, these results demonstrate significant parallels between γ/δ and α/β lineage development, and suggest a general role for TCR signaling in thymic maturation.