Antigen Presentation to Lymphocytes thymic T cells evcompmiTncbattiognire The amount ly and the avidity of antigens d to matu sitive ted in to ll ar ith p avidity fail to induce negative selection of T cells in thymus and B cells in bone marrow,and may induce tolerance rather than an ce mmune response in the periphery. nic apc negative selec Tcells for selection.Those escaping negative selection are likely to be Costimulatory molecules on APCs anergized in the periphery,in part through interaction with peripheral that )by selection in thymus are described separately. d pa 997.An lymphocytes (Var APCsmuates TccllstoexprC4 gand.whic Other APCs then binds to CD40 expressed by APCs.CD40 ligation on inte n with CD2 this case B cells can capture even minute quantities of on T cells.In the absence of CD40 or other acc antigens compared to other APCs(Townsend and Good- molecules,APCs have been shown to anergize T cells as now, 1998).Bone Cs appear to be gan ing the nha significance of CD40 in initiating T-cell activation. APCs found in the lymphoid tissues there are a larg number of potential APCs in the body.These include Kupffer er microglias in br in,follicular cells B cells as APCs connectiv ssues and Altho tation by bcells is no acquire the ability to present antigen therHC molecules are induced and expressed.Presentation of self dendritic cells,Bcells b ent AP n antigens antigens by such cells may be involved in the development hn be come zed by t T of autoimmunity nder in ondition.while stimulation of Bcels by CD40 ligand,BCR crosslinking or cytokines,greatly Activation versus Nonactivation hances t entieemcgentetomeSonaredpithotheT s,antigen-spe en BCR.even The consequence ofantigen presentation to lvmphocvtes is has been shown that activated.antiger influenced by several factors, including the site of cells present antigen toTcells and trigger proliferation and presentation.the amount and av vidity of an gens,and the cytokine secretion.However,i ma d contras tory mole Its from a num di with 19061A dictates the fate of developing and B cells.T cells in the induces tolerance or anergy rather than activation of T thymus recognizing self antigen-MHC complexes with high affinity are deleted of antigen fror n antigen-specin high attinity the periphery.Tand B cells are activated if they re leads tot antigens with high affinity.The T or B cells recognizing by rapid disappearance of the T cells (Townsend and athnity are either nonresponsive or Goodno 998)】 nization of an t on ly pre le antigenicpeptide same antigen may induce anergy or peripheral tolerance but also regulate T-cell activation by supplying costimu- against the antigen.The exact molecular mechanism for latory signals.Antigen presentation thus constitutes a such differential responses remains obscure. the initiation of 4 ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group /www.els.net thymic T cells. Developing thymic T cells that recognize self antigen–MHC complexes with moderate affinity are allowed to mature (a process called positive selection) while those recognizing self antigen–MHC complexes with high affinity are deleted to prevent the maturation of self￾reactive T cells (a process called negative selection). It is unlikely, though, that thymic APCs can present all the self antigens to developing T cells for positive and negative selection. Those escaping negative selection are likely to be anergized in the periphery, in part through interaction with peripheral APCs that lack costimulatory molecules. Precise molecular mechanisms of positive and negative selection in thymus are described separately. Other APCs B lymphocytes found in spleen and lymph nodes are efficient APCs, especially when they recognize antigens. In this case, B cells can capture even minute quantities of antigens compared to other APCs (Townsend and Good￾now, 1998). Bone marrow-derived APCs appear to be required for the activation of cytotoxic T cells against viruses that infect nonhaematopoietic cells. Besides the APCs found in the lymphoid tissues, there are a large number of potential APCs in the body. These include Kupffer cells in the liver, microglias in brain, follicular cells in thyroid and fibroblasts in connective tissues and endothelial cells. Furthermore, other cell types may acquire the ability to present antigen if their MHC molecules are induced and expressed. Presentation of self antigens by such cells may be involved in the development of autoimmunity. Activation versus Nonactivation The consequence of antigen presentation to lymphocytes is influenced by several factors, including the site of presentation, the amount and avidity of antigens, and the presence or absence of costimulatory molecules expressed by APCs (Goodnow, 1996). Antigen presentation by APCs dictates the fate of developing T and B cells. T cells in the thymus recognizing self antigen–MHC complexes with high affinity are deleted. Likewise, immature B cells in the bone marrow that recognize self antigens with high affinity are eliminated. By contrast to thymus and bone marrow, in the periphery, T and B cells are activated if they recognize antigens with high affinity. The T or B cells recognizing antigens with low affinity are either nonresponsive or anergized. While intraperitoneal immunization of antigens induces an immune response, oral administration of the same antigen may induce anergy or peripheral tolerance against the antigen. The exact molecular mechanism for such differential responses remains obscure. The amount and the avidity of antigens presented to lymphocytes also influence immune responses. Antigens presented in too small amounts or with too low avidity fail to induce negative selection of T cells in thymus and B cells in bone marrow, and may induce tolerance rather than an immune response in the periphery. Costimulatory molecules on APCs Expression of costimulatory molecules such as CD40 by APCs is essential in the activation of lymphocytes (Van Kooten and Banchereau, 1997). Antigen presentation by APCs stimulates T cells to express CD40 ligand, which then binds to CD40 expressed by APCs. CD40 ligation on APCs induces the expression of costimulatory molecules such as CD80 (B7-1) and CD86 (B7-2), which then further stimulate T-cell activation through interaction with CD28 on T cells. In the absence of CD40 or other accessory molecules, APCs have been shown to anergize T cells. Blockage of CD40–CD40 ligand interaction in vivo, as shown in either CD40- or CD40 ligand-deficient mice, abrogates humoral immune responses, demonstrating the significance of CD40 in initiating T-cell activation. B cells as APCs Although in general, antigen presentation by B cells is not as efficient as that by professional APCs, such as activated dendritic cells, B cells become efficient APCs when antigens can be recognized by the BCR. Resting B cells have been shown to induce partial activation or anergy of T cells underin vitro culture condition, while stimulation of B cells by CD40 ligand, BCR crosslinking or cytokines, greatly enhances the antigen presentation. Compared with other APCs, antigen-specific B cells can efficiently capture even small amounts of antigens through their BCR. In fact, it has been shown in vitro that activated, antigen-specific B cells present antigen to T cells and trigger proliferation and cytokine secretion. However, in marked contrast with in vitro studies, results from a number of in vivo studies have shown that B-cell presentation of antigen to cognate T cells induces tolerance or anergy rather than activation of T cells. Direct presentation of antigen by B cells or by transfer of antigen from antigen-specific B cells to endogenous antigen-presenting cells induces abortive proliferation of T cells. It appears that antigen presentation by B cells in vivo leads to the initial proliferation of T cells, which is followed by rapid disappearance of the T cells (Townsend and Goodnow, 1998). In conclusion, APCs not only provide antigenic peptides in association with MHC molecules for T-cell recognition, but also regulate T-cell activation by supplying costimu￾latory signals. Antigen presentation thus constitutes a fundamental step in the initiation of an immune response. Further studies on the mechanisms of differential immune Antigen Presentation to Lymphocytes 4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net