A fundamental tenet of immunology is the requirement for dual receptor engagement of the T cell by an APC in order to achieve full activation. In addition to signaling through the TCR by peptide/MHC (signal 1), simultaneous ligation at a different site (signal 2), particularly CD28 on the T-cell membrane by the B7 family of ligands (CD80 and CD86), on the APC generally must occur. If costimulation does not occur, engagement of the TCR by a high-affinity ligand produces a long-lasting state of paralysis. Upon subsequent challenge with cognate antigen by "professional" APCs, i.e., cells expressing costimulatory molecules, T cells in this anergic state will not transcribe certain cytokines (most notably IL-2), will not respond to other T-cell growth factors, and will not proliferate . Anergic T cells are deficient in helper activity for B cells but are not dead; they remain viable for an indefinite time and can be made to proliferate in vitro and provide helper activity with cognate antigen in the presence of high concentrations of IL-2 [59, 60]. Anergy is widely believed to be an important mechanism for peripheral T-cell tolerance because it is likely that autoreactive T cells could encounter their cognate antigen on nonprofessional APCs or immature dendritic cells that lack costimulatory function. In addition, various experimental protocols have been devised based on the concept of anergy in hopes of inducing tolerance to self-antigens and ameliorating autoimmune disease.
Unfortunately, T-cell anergy, as defined by non-responsiveness after signal 1-only, does not occur with naïve T cells. Prior studies on T-cell anergy have typically involved T-cell lines or clones, which are similar in phenotype to memory (antigen-experienced) T cells. Naïve T cells are insensitive to anergy induction in vitro and may even proliferate in response to signal 1-only, such as via anti-CD3 . In vivo, transfer of naïve T cells from TCR transgenic mice into a host expressing the cognate antigen in a non-inflammatory environment [1, 28, 32] or on mature dendritic cells in the presence or absence of the costimulatory molecules B7-1 and B7-2  or CD40  initially results in activation and proliferation of the transgenic T cells, not anergy. Claims that naïve T cells can be anergized in vitro or in vivo typically involve experimental conditions in which the cells were forced to divide at least once or conditions in which a different form of T-cell tolerance was acting, such as T-cell adaptation to create Tregs, activation-induced cell death (see below), or engagement of cytotoxic T lymphocyte-antigen 4 (CTLA-4). It has been speculated that lipid rafts, which contain a variety of src-family kinases, must first be mobilized to the cell membrane in response to initial contact with antigen before the anergy-inducing machinery can function .
CTLA-4 is a ligand for B7 that is upregulated upon T-cell activation and that attenuates costimulation through CD28. Mice lacking functional CTLA-4 display massive lymphocyte activation and die of multi-organ lymphocyte infiltrates suggestive of systemic autoimmunity . Blockage of B7 — CD28 signaling by therapeutic introduction of soluble CTLA-4-Ig prolongs allograft survival , inhibits disease progression and autoantibody load in murine lupus , and has been used successfully to treat psoriasis . While upregulation and engagement of CTLA-4 are important mechanisms to terminate T-cell activation, these processes do not appear to cause permanent T-cell tolerance or to distinguish self from foreign antigen responses.
Overall, T-cell anergy in the periphery is not a dependable mechanism for preventing autoimmunity. Even if anergy could be induced in naïve autoreactive T cells, the first APC presenting the cognate self-antigen to a newly emerging T cell would have to be immature or nonprofessional without costimulatory molecules. However, there is no known compartmentalization of nascent, mature T cells in either the thymus, where professional APCs in the form of dendritic cells commonly coexist , or when they enter the circulation as naïve T cells and could potentially encounter any type of APC, including activated dendritic cells with full costimulation function (reviewed in ). A similar problem would be faced by an autoreactive T cell that was somehow activated and developed into a clone of memory T cells without causing disease and for some reason needed to be suppressed to avoid future pathology: while capable of being anergized, this process would require signaling through the TCR by a nonprofessional APC. The dilemma is that efficient presentation of antigen by professional APCs is an essential feature of a useful immune system, and functional APCs are constitutively available to endocytose and cross-present antigen whether from a foreign source or from shed self-material or dead cell debris. Discrimination between self and dangerous insults is greatly enhanced by the Toll-like receptors for "pathogen-associated recognition patterns" expressed on dendritic cells, resulting in maturation, cytokine and chemokine secretion, and enhanced survival of these APCs . However, cross-presentation of self-antigens readily occurs, as demonstrated by adoptive transfer studies in which naïve TCR-transgenic T cells become activated when exposed to cognate antigen synthesized in non-lymphoid cells in a non-inflammatory environment [1, 28, 32, 62]. In a normal setting, central T-cell tolerance would avert such an autoim mune response. Although T-cell anergy is a very real phenomenon that can be manifested during positive selection in the thymus or experimentally by memory T cells in the periphery or by T-cell clones in vitro, there is considerable doubt about the physiological significance of peripheral anergy in preventing autoimmunity.
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