During activation, T cells express receptors for receiving positive and negative costimulatory signals. Here we identify the B and T lymphocyte attenuator (BTLA), an immunoglobulin domain-containing glycoprotein with two immunoreceptor tyrosine-based inhibitory motifs. BTLA is not expressed by naive T cells, but it is induced during activation and remains expressed on T helper type 1 (T(H)1) but not T(H)2 cells. Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and association with the Src homology domain 2 (SH2)-containing protein tyrosine phosphatases SHP-1 and SHP-2, and attenuates production of interleukin 2 (IL-2). BTLA-deficient T cells show increased proliferation, and BTLA-deficient mice have increased specific antibody responses and enhanced sensitivity to experimental autoimmune encephalomyelitis. B7x, a peripheral homolog of B7, is a ligand of BTLA. Thus, BTLA is a third inhibitory receptor on T lymphocytes with similarities to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1).

The PD-1 receptor and ligands PD-L1 and PD-L2, members of the CD28 and B7 families, play critical roles in T cell coinhibition and exhaustion. Overexpression of PD-L1 and PD-1 on tumor cells and tumor-infiltrating lymphocytes, respectively, correlates with poor disease outcome in some human cancers. Monoclonal antibodies (mAbs) blockading the PD-1/PD-L1 pathway have been developed for cancer immunotherapy via enhancing T cell functions. Clinical trials with mAbs to PD-1 and PD-L1 have shown impressive response rates in patients, particularly for melanoma, non-small-cell lung cancer, renal cell carcinoma, and bladder cancer. Further studies are needed to dissect mechanisms of variable response rate, to identify biomarkers for clinical response, to develop small molecule inhibitors, and to combine with other therapies.

B7 family proteins provide costimulatory signals that regulate T cell responses. Here we report the third set of B7 family-related T cell inhibitory molecules with the identification of a homolog of the B7 family, B7x. It is expressed in immune cells, nonlymphoid tissues, and some tumor cell lines. B7x inhibits cell-cycle progression, proliferation, and cytokine production of both CD4 ؉ and CD8 ؉ T cells. B7x binds a receptor that is expressed on activated, but not resting T cells that is distinct from known CD28 family members. Its receptor may be a recently identified inhibitory molecule, B and T lymphocyte attenuator. These studies identify a costimulatory pathway that may have a unique function in down-regulation of tissue-specific autoimmunity and antitumor responses.costimulation ͉ autoimmunity ͉ tumor

B7-H3 (CD276) is an important immune checkpoint member of the B7 and CD28 families. Induced on antigen presenting cells, B7-H3 plays an important role in the inhibition of T cell function. Importantly, B7-H3 is highly overexpressed on a wide range of human solid cancers and often correlates with both negative prognosis and poor clinical outcome in patients. Challenges remain to identify the receptor(s) of B7-H3 and thus better elucidate the role of the B7-H3 pathway in immune responses and tumor evasion. With a preferential expression on tumor cells, B7-H3 is an attractive target for cancer immunotherapy. Based on the clinical success of inhibitory immune checkpoint blockade (CTLA-4, PD-1 and PD-L1), developing monoclonal antibodies (mAbs) against B7-H3 appears promising therapeutic strategies. An unconventional mAb against B7-H3 with antibody-dependent cell-mediated cytotoxicity is currently being evaluated in a Phase I clinical trial and has shown encouraging preliminary results. Additional therapeutic approaches in targeting B7-H3, such as blocking mAbs, bispecific mAbs, chimeric antigen receptor T cells, small molecules inhibitors, and combination therapies should be evaluated as these technologies have already shown positive results in various cancer settings. A better understanding of the B7-H3 pathway in humans will surely help to further optimize associated cancer immunotherapies.