Mutation of the Polyproline Sequence in CD3ε Evidences TCR Signaling Requirements for Differentiation and Function of Pro-Inflammatory Tγδ17 Cells

T gamma delta 17 cells have emerged as a key population in the development of inflammatory and autoimmune conditions such as psoriasis. Thus, the therapeutic intervention of T gamma delta 17 cells can exert protective effects in this type of pathologies. T gamma delta cells commit to IL-17 production during thymus development, and upon immune challenge, additional extrathymic signals induce the differentiation of uncommitted T gamma delta cells into T gamma delta 17 effector cells. Despite the interest in T gamma delta 17 cells during the past 20 years, the role of TCR signaling in the generation and function of T gamma delta 17 cells has not been completely elucidated. While some studies point to the notion that T gamma delta 17 differentiation requires weak or no TCR signaling, other works suggest that T gamma delta 17 require the participation of specific kinases and adaptor molecules downstream of the TCR. Here we have examined the differentiation and pathogenic function of T gamma delta 17 cells in knockin mice bearing conservative mutations in the CD3 epsilon polyproline rich sequence (KI-PRS) with attenuated TCR signaling due to lack of binding of the essential adaptor Nck. KI-PRS mice presented decreased frequency and numbers of T gamma delta 17 cells in adult thymus and lymph nodes. In the Imiquimod model of skin inflammation, KI-PRS presented attenuated skin inflammation parameters compared to wild-type littermates. Moreover, the generation, expansion and effector function T gamma delta 17 cells were impaired in KI-PRS mice upon Imiquimod challenge. Thus, we conclude that an intact CD3 epsilon-PRS sequence is required for optimal differentiation and pathogenic function of T gamma delta 17 cells. These data open new opportunities for therapeutic targeting of specific TCR downstream effectors for treatment of T gamma delta 17-mediated diseases.

Automated summary

T gamma delta 17 cells play a key role in inflammatory and autoimmune diseases. The role of TCR signaling in the generation and function of T gamma delta 17 cells is not fully understood. The intact CD3 epsilon-PRS sequence is required for optimal differentiation and pathogenic function of T gamma delta 17 cells.