Introduction: T cells use a variety of mechanisms to regulate each other and maintain immune homeostasis. We recently reported that activated T cells suppress each other by releasing the GPI-anchored glycoprotein CD52, which then binds to the inhibitory Siglec-10 (sialic acid binding Ig-like lectin-10) receptor (1). Siglec-10 has been reported to bind to another GPI glycoprotein, CD24, pre-complexed with HMGB1 (2). Objective: To determine if the interaction of CD52 with Siglec-10 requires HMGB1. Methods: Binding studies of recombinant CD52-Fc, Siglec-10-Fc and HMGB1 proteins were performed in microtiter ELISA plates. Recruitment of CD52-HMGB1-Siglec-10 complex after engagement of TCR was analysed by immunoprecipitation and Western blotting using protein lysates from the human Jurkat cell line and blood CD4+ T cells from healthy individuals. Results: Whole HMGB1 and HMGB1 Box B, but not Box A, bound to CD52-Fc, and was required for CD52 binding to Siglec-10. HMGB1, CD52-Fc and Siglec-10 are complexed together after activation with anti-CD3 binding to the TCR with failure to phosphorylate TCR-associated tyrosine kinases Lck and Zap70. Conclusions: Binding of CD52 to Siglec-10 requires pre-complexing of CD52 to HMGB1. This mechanism not only captures HMGB1 present in serum to abrogate its pro-inflammatory effect but leads to a concerted anti-inflammatory effect mediated via Siglec-10 where HMGB1 seems to be an important requirement for inactivation of TCR signaling.
1) Bandala-Sanchez E., Zhang Y., Reinwald S., Dromey JA., Lee B-H., Qian J., Bohmer RM and Harrison LC. T cell regulation mediated by interaction of soluble CD52 with the inhibitory receptor Siglec-10. Nat Immunol. 14: 741-8 (2013).
2) Chen, G. Y., Tang, J., Zheng, P. and Liu Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 323: 1722-1725 (2009).