| First Author | Borroto A | Year | 2022 |
| Journal | Front Immunol | Volume | 13 |
| Pages | 799919 | PubMed ID | 35432331 |
| Mgi Jnum | J:323920 | Mgi Id | MGI:7263738 |
| Doi | 10.3389/fimmu.2022.799919 | Citation | Borroto A, et al. (2022) Mutation of the Polyproline Sequence in CD3epsilon Evidences TCR Signaling Requirements for Differentiation and Function of Pro-Inflammatory Tgammadelta17 Cells. Front Immunol 13:799919 |
| abstractText | Tgammadelta17 cells have emerged as a key population in the development of inflammatory and autoimmune conditions such as psoriasis. Thus, the therapeutic intervention of Tgammadelta17 cells can exert protective effects in this type of pathologies. Tgammadelta cells commit to IL-17 production during thymus development, and upon immune challenge, additional extrathymic signals induce the differentiation of uncommitted Tgammadelta cells into Tgammadelta17 effector cells. Despite the interest in Tgammadelta17 cells during the past 20 years, the role of TCR signaling in the generation and function of Tgammadelta17 cells has not been completely elucidated. While some studies point to the notion that Tgammadelta17 differentiation requires weak or no TCR signaling, other works suggest that Tgammadelta17 require the participation of specific kinases and adaptor molecules downstream of the TCR. Here we have examined the differentiation and pathogenic function of Tgammadelta17 cells in "knockin" mice bearing conservative mutations in the CD3epsilon 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 Tgammadelta17 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 Tgammadelta17 cells were impaired in KI-PRS mice upon Imiquimod challenge. Thus, we conclude that an intact CD3epsilon-PRS sequence is required for optimal differentiation and pathogenic function of Tgammadelta17 cells. These data open new opportunities for therapeutic targeting of specific TCR downstream effectors for treatment of Tgammadelta17-mediated diseases. |
