Pic originally identified in Shigella flexneri 2a and EAEC, was found to cleave mucin from numerous sources, to induce mucus release, and to confer a subtle competitive advantage in mucosal colonization. We recently showed that Pic and Tsh/Hb cleave a variety of leukocyte surface glycoproteins with diverse roles in numerous cellular and immune functions, and which were substituted with carbohydrates structurally similar to those found on human mucin glycoproteins. More importantly, cleavage of those glycoproteins triggered adverse effects on leukocyte functions such as chemotaxis, transmigration, activation and apoptosis. Therefore, we have proposed a main role for Pic and Tsh/Hbp in immune evasion. Here, we show that the class-2 SPATE GDC-0810 family shares a lectin-like property and have proteolytic activity against a large variety of O-linked glycoproteins in the hematopoietic cell lineage, and in both, innate and adaptive immunity. We previously showed that Pic and Tsh/Hbp were able to cleave O-linked glycoproteins such as CD43, CD44, CD45, CD93, CD162 and CX3CL on human neutrophils and lymphocytes. Here we tested all other class-2 SPATEs on the same and new glycoproteins involved in diverse functions of the immune system. Three mg of glycoproteins were incubated with 2 mM of each SPATE for 1 h at 37uC, and analyzed by SDSPAGE and Commassie staining. We found that most class-2 SPATEs tested Diethylmaleate except SepA, EpeA or the Pic258A mutant efficiently cleaved the substrates mentioned above, and many others including CD34, CD55, CD164, TIM1, TIM2, TIM3 and C1-INH, all of them known to possess O-linked carbohydrates. Pic, PicU and Crc2sp showed the most astringent protease activity as we noticed extensive cleavage in almost all glycoproteins tested. Tsh/Hbp and Vat-Ex showed comparable activities. The differential cleavage pattern seen on glycoproteins could be explained by the glycosylation level of the molecules, as some glycoproteins such as CD43, CD93, CD162 and CX3CL are known to be extensively O-glycosylated, and which were almost completely digested by SPATEs, suggesting the presence of multiple cleavage sites.