Differential effect of CD69 targeting on bystander and antigen-specific T cell proliferation

CD69 targeting induces bystander T cell proliferation but does not affect antigen‐specific proliferation. In spite of an initially proposed role as a costimulatory molecule for CD69, in vivo studies showed it as a regulator of immune responses and lymphocyte egress. We found constitutive CD69 expression by T cell subsets and pDC. We examined a possible effect of CD69 on T cell proliferation using transfer models and in vitro assays. In mice locally expressing or receiving antigen, anti‐CD692.2 treatment did not affect the proliferation of antigen‐specific transgenic T cells in ADLN, although we observed the presence of proliferated T cells in non‐ADLN and spleen. This was not affected by FTY720 treatment and thus, not contributed by increased egress of proliferated lymphocytes from ADLN. In the absence of antigen, anti‐CD69 2.2 treatment induced bystander proliferation of transferred memory phenotype T cells. This proliferation was mediated by IL‐2, as it was inhibited by anti‐IL‐2 or anti‐CD25 antibodies in vitro and by anti‐CD25 antibodies in vivo. It was also dependent on CD69 expression by donor T cells and recipient cells. CD69 targeting on T cells enhanced IL‐2‐mediated proliferation and CD25 expression. However, it did not lead to increased early IL‐2 production by T cells. No T cell subset was found to be specifically required in the recipient. Instead, CD69 targeting on pDC induced their expression of IL‐2 and CD25, and pDC depletion showed that this subset was involved in the proliferation induction. These results indicate that CD69 targeting induces bystander T cell proliferation through pDC IL‐2 production and T cell sensitization to IL‐2 without affecting antigen‐driven T cell proliferation.