Alpha-beta T cell positive selection is enhanced by CD3-delta via a quantitative developmental signaling mechanism

Abstract

Abstract CD3-delta has a critical role in alpha-beta T cell development; its absence greatly diminishes thymocyte positive selection. Despite this critical role, mice lacking CD3-delta have a low, but reproducible numbers of peripheral alpha-beta T cells, indicating that some T cell development occurs independently of CD3-delta. These T cells lacking CD3-delta developed via positive selection as evidenced by genetic Major Histocompatibility Complex-dependence, progression to single positive thymocytes in fetal thymic organ culture and the presence of functional immune responses in vivo. Given this data, CD3-delta must have either a qualitative or quantitative impact on positive selection. Specifically, a qualitative impact would mean that CD3-delta is required for a subset of T cell receptors (TCRs) to be selected, resulting in a starkly skewed TCR repertoire with corresponding absolute deficiencies in certain immune responses, or an altered immunodominance to specific infection. In contrast, a quantitative role in positive selection would show a conserved, diverse peripheral TCR repertoire with a decreased quantity of each TCR clone paired with present, though decreased, immune responses. The TCR repertoire complexity of T cells lacking CD3-delta was complex for both alpha and beta transcripts, likely indicating a quantitative role. Similarly, in vivo, mice lacking CD3-delta responded effectively to three independent immune challenges. These findings indicate that the CD3-delta protein quantitatively increases the efficiency of positive selection, likely through enhanced signal amplification, allowing the alpha-beta T cell pool to be more efficiently generated.