Engagement of distinct epitopes on CD43 induces different co-stimulatory pathways in human T cells.

Co-receptors, being either co-stimulatory or co-inhibitory, play a pivotal role in T-cell immunity. Several studies have indicated that CD43, one of the abundant T-cell surface glycoproteins, acts not only as a potent co-receptor but also as a negative regulator for T-cell activation. Here we demonstrate that co-stimulation of human peripheral blood (PB) T cells through two distinct CD43 epitopes recognized by monoclonal antibodies (mAb) CD43-6E5 (T(6E5-act) ) and CD43-10G7 (T(10G7-act) ) potently induced T-cell proliferation. However, T-cell co-stimulation through two CD43 epitopes differentially regulated activation of nuclear factor of activated T cells (NFAT) and nuclear factor-κB (NF-κB) transcription factors, T-cell cytokine production and effector function. T(6E5-act) produced high levels of interleukin-22 (IL-22) and interferon-γ (IFN-γ) similar to T cells activated via CD28 (T(CD)(28-act) ), whereas T(10G7-act) produced low levels of inflammatory cytokines but higher levels of regulatory cytokines transforming growth factor-β (TGF-β) and interleukin-35 (IL-35). Compared with T(6E5-act) or to T(CD)(28-act) , T(10G7-act) performed poorly in response to re-stimulation and further acquired a T-cell suppressive function. T(10G7-act) did not directly inhibit proliferation of responder T cells, but formed stable heterotypic clusters with dendritic cells (DC) via CD2 to constrain activation of responder T cells. Together, our data demonstrate that CD43 is a unique and polarizing regulator of T-cell function.