Mannan binding lectin (MBL), initially reported to activate the complement pathway, is also known to be involved in the pathogenesis of autoimmune diseases. We report a thus far unknown function of MBL as a suppressor of T‐cell activation. MBL markedly inhibited T‐cell proliferation induced by anti‐CD3 and anti‐CD28 antibodies. Moreover, the presence of MBL during T‐cell priming interfered with proximal T‐cell receptor signaling by decreasing phosphorylation of Lck, ZAP‐70, and LAT. MBL bound to T cells through interaction between the collagen‐like region of MBL and calreticulin (CRT) expressed on the T‐cell surface. The neutralizing antibody against CRT abrogated MBL‐mediated suppression of T‐cell proliferation, suggesting that MBL down‐modulates T‐cell proliferation via cell surface CRT. We further demonstrated that the feature of MBL‐mediated T‐cell suppression is shared by other serum collectins (e.g., C1q and collectin 11). The concentrations of MBL correlated negatively with in vivo T‐cell activation status in patients with early‐stage silicosis. Furthermore, MBL efficiently inhibited activation and proliferation of autoreactive T cells derived from patients with silicosis, indicating that MBL serves as a negative feedback control of the T‐cell responses.—Zhao, N., Wu, J., Xiong, S., Zhang, L., Lu, X., Chen, S., Wu, Q., Wang, H., Liu, Y., Chen, Z., Zuo, D. Mannan‐binding lectin, a serum collectin, suppresses T‐cell proliferation via direct interaction with cell surface calreticulin and inhibition of proximal T‐cell receptor signaling. FASEB J. 31, 2405–2417 (2017). www.fasebj.org