The B7–CD28 superfamily

The B7-1/B7-2–CD28/CTLA-4 co-stimulatory pathway has a crucial role in regulating T-cell activation and tolerance. New B7 and CD28 family members and new pathways have recently been identified that seem to be especially important for regulating the responses of previously activated, rather than antigen-inexperienced, T cells. B7-1 and B7-2 are expressed on professional antigen-presenting cells (APCs), with B7-2 being expressed earlier. B7-2 is more important than B7-1 in initiating T-cell responses. The new B7 homologues are also expressed on cells other than professional APCs, indicating that there might be new mechanisms for regulating T-cell responses in peripheral tissues. In contrast to the constitutive expression of CD28, the CD28 homologue ICOS is induced rapidly on T cells after TCR engagement. ICOS expression is stimulated by both TCR and CD28 signals. The ligand for ICOS (ICOSL) is expressed at low levels on resting B cells, some macrophages and dendritic cells, and can be induced by IFN-γ. ICOSL is also expressed on other cell types, including fibroblasts. Although the signals through CD28 are crucial for the initial co-stimulation of interleukin 2 (IL-2) production, ICOS signals only modestly influence T-cell proliferation and IL-2 production. ICOS signals are most important for regulating cytokine production by recently activated and effector T cells: ICOS can regulate both TH1 and TH2 effector cytokine production, and it has a particularly important role in regulating IL-10 production. ICOS has a crucial role in T-cell–B-cell collaboration and promotes immunoglobulin isotype class switching and germinal centre formation The CD28 family member PD-1 is inducibly expressed on T cells, B cells and myeloid cells, and has an ITIM/ITSM motif in its cytoplasmic domain that recruits SHP-2. PD-1-deficient mice develop late-onset progressive arthritis, lupus-like glomerulonephritis and myocarditis, showing that PD-1 has a role in downregulating immune responses. PD-1 binds to two B7 homologues, PD-L1 (B7-H1) and PD-L2 (B7-DC), but not to other B7 family members. The PD-1 ligands bind to PD-1 but no other CD28 family members. PD-L1 and PD-L2 are expressed in lymphoid and non-lymphoid tissues, and in some tumours. PD-L1 and PD-L2 can inhibit proliferation and cytokine production by previously activated T cells, and can antagonize a B7-2 signal when antigenic stimulation is weak or limiting. Like CTLA-4, PD-1 engagement can lead to cell cycle arrest. Some studies support a role for PD-L1 and PD-L2 in stimulating T-cell responses.