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.