The complexities of CD28 and CTLA-4 signalling: PI3K and beyond.
A successful immune response requires a set of non-cognate cell-cell interactions which provide the second "costimulatory" signal to the T cells. The best characterized costimulatory receptor expressed on resting T cells is CD28 which provides poorly-defined cyclosporin-resistant biochemical signal(s) that promote expression of several cytokines/chemokines. Another major effect of CD28 ligation is the promotion of cell survival which is thought to occur via the up-regulation of Bcl-xL expression, CD28 shares its ligands B7.1 and B7.2 with the related CTLA-4, which plays an inhibitory role in T cell activation. Manipulation of CD28/CTLA-4 interactions with their natural ligands has provided exciting results in transplantation and tumor therapy settings and also has potential in the treatment of several diseases such as arthritis and multiple sclerosis, asthma and protection against HIV infection. The biochemical basis for the different functional outcomes of CD28 and CTLA-4 ligation has been the subject of intense investigation over the past few years. This review will focus on our current understanding of the biochemical signals that may be involved in regulating the different functional outcomes of CD28 and CTLA-4, with particular emphasis on the role played by the PI3K-dependent signalling cascade.
Ward
S G
SG
Department of Pharmacy and Pharmacology, Bath University, Claverton Down, United Kingdom.
D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D018106:CD28 Antigens / Q000737:chemistry / Q000502:physiology*; D060908:CTLA-4 Antigen; D006801:Humans; D018796:Immunoconjugates; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D000069594:Abatacept; D019869:Phosphatidylinositol 3-Kinases