Immunology, T cell, CD28, CTLA4, Co-stimulation, B7, CD80, CD86, Immune tolerance
T lymphocytes in peripheral lymphoid tissues are inactive cells that must receive receptor-initiated signals to become activated and participate in an antigen specific immune response. The integration of intracellular signals from the antigen receptor and from one or more costimulatory receptors can stimulate cell division, cytokine production, differentiation and activation of effector cell functions in T lymphocytes. Positive and negative signals from various costimulatory receptors contribute to a dynamic T lymphocyte-mediated response when the immune system is challenged by a pathogen. CD28 is the primary costimulatory receptor in na´ve T cells and it is activated by engaging B7-1 (CD80) or B7-2 (CD86) ligands on antigen presenting cells. The integration of signals from coengagement of TCR (signal #1) and CD28 (signal #2) receptors produces high levels of IL-2 production, augmented proliferation and provides essential survival signals for T lymphocytes. In the absence of signal #2, TCR signals are insufficient to fully stimulate previously unstimulated(na´ve) T lymphocytes to undergo clonal expansion and differentiation and these T cells can become anergic.1 Although previously stimulated (secondary) T lymphocytes also can respond to CD28 costimulatory signals, this costimulatory response is lost after successive rounds of antigen stimulation. While CD28 is the best-characterized costimulatory receptor, other CD28 family members (inducible costimulator (ICOS), cytotoxic T lymphocyte antigen-4 (CTLA-4; CD152), programmed death 1 (PD-1), the uncharacterized receptor for B7-H3) and TNF receptor family members (4-1BB, OX-40, HVEM) can differentially augment or inhibit select components of the activation response in secondary T lymphocytes. This review will focus on identifying the intracellular signaling events initiated by ligation of CD28 receptor and CTLA-4 receptors.