CD28 was initially identified by antibodies as a 44 kD protein on the membrane of human T cells. CD28 is a 23 kD glycosylated type 1 transmembrane protein, which forms a disulfide-linked homodimer. CD28 is a costimulatory receptor that synergizes with TCR-mediated signals to enhance cytokine production and the proliferation of T cells. CD28 plays a primordial role for the priming of naive T cells. CD28, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152), inducible costimulatory (ICOS), programmed death receptor 1 (PD-1), and B- and T-lymphocyte attenuator (BTLA) are members of the family of costimulatory receptors. CD28 and CTLA-4 both bind the same ligands B7-1 (CD80) and B7-2 (CD86). CD28 and ICOS mainly induce T-cell activation while as CTLA-4, PD-1, and BTLA are inhibitory. In murine plasmacytoid dendritic cells, CD28 signaling induces the downregulation of type I interferon production, which contrasts with its activation role in T cells. CD28 is also expressed on normal murine and human plasma cells (PCs). It promotes PC survival, sustained antibody responses, and the upregulation of transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1), which is a master regulator of PC differentiation. CD28 is also expressed in malignant BM-resident PC of multiple myeloma (MM) and its overexpression in myeloma cells is associated to bad prognostics. The soluble costimulatory molecule CD28 has been detected in the serum of patients with systemic lupus erythematosus, primary Sj?gren's syndrome, and systemic sclerosis. Soluble CD28 results from the shedding of the membrane-bound form.