T-cell costimulation and coinhibition in atherosclerosis.
Evidence from many human and rodent studies has established that T lymphocytes enhance inflammation in atherosclerotic plaques and contribute to lesion progression and remodeling. Recent work also indicates that regulatory T cells are important in limiting proatherogenic T-cell responses. Given the important role of T cells in atherosclerosis, there is a need to fully understand how proatherogenic T cells are activated and regulated. Antigen-dependent activation of naïve T cells, leading to clonal expansion and effector T-cell differentiation, and effector and memory T cells, is enhanced by signals provided by costimulatory molecules expressed by antigen presenting cells, which bind to receptors on the T cells. In addition, T-cell responses to antigen are negatively regulated by coinhibitory molecules expressed by antigen-presenting cells, which bind to receptors on T cells. Two major families of costimulatory molecules include the B7 and the tumor necrosis factor (TNF) families. These molecules bind to receptors on T cells belonging to the CD28 or TNF receptor families, respectively. The best-defined coinhibitors and their receptors belong to the B7 and CD28 families. Recent work has begun to define how these T-cell costimulatory and coinhibitory pathways influence atherosclerosis, largely in mouse models of the disease. Profound effects are attributable to molecules in both the B7/CD28 (B7-1/2, ICOS, and PDL-1/2) and the TNF/TNF receptor (CD40, OX40, and CD137) families. One emerging theme is that both pathogenic effector T-cell responses and regulatory T cells are influenced by overlapping sets of costimulators and coinhibitors. These complexities must be considered as immunotherapeutic approaches for atherosclerotic disease are developed.
Gotsman
Israel
I
Heart Institute, Hadassah University Hospital, Jerusalem.
Sharpe
Arlene H
AH
Lichtman
Andrew H
AH
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D018106:CD28 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D002454:Cell Differentiation; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D051379:Mice; D023421:Models, Animal; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D015703:Antigens, CD; D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand