unresponsive (anergic) or undergo apoptosis. The second signal involves binding of costimulatory molecules (CD40, CD80 [also known as B7-1], and CD86 [also known as B7-2]) on the APC to their respective ligands (CD40L for CD40, CD28 for CD80 or CD86). Activation of T cells is regulated via a negative feedback loop involving another molecule known as T-lymphocyte– associated antigen 4 (CTLA-4). Following engagement of CD28 with CD80 or CD86, CTLA-4 in the cytoplasm is mobilized to the cell surface where, because of its higher affinity of binding to CD80 and CD86, it outcompetes or displaces CD28 resulting in suppression of T-cell activation and proliferation. This property of CTLA-4 has been exploited as a strategy for sustaining a desirable immune response such as that directed against cancer. A recombinant humanized antibody (ipilimumab) that binds CTLA-4 prevents its association with CD80/CD86. In so doing, the activated state of T cells is sustained. Programmed cell death protein-1 (PD-1) is another negative regulator of T cells. Ligation of PD-1 with its ligands (PD-L1 or PD-L2) suppresses T-cell activity. Like CTLA-4, Mabs have been developed to block the interaction of PD-1 with PD-L1, having the effect of sustained T cell activation. Mabs to CTLA-4 and PD-1/PD-L1 are immune checkpoint inhibitors. They have been associated in some patients with the development of autoimmune toxicity that subsides upon discontinuation of Mab therapy.
T lymphocytes develop and learn to recognize self and non-self antigens in the thymus; those T cells that bind with high affinity to self antigens in the thymus undergo apoptosis (negative selection), while those that are capable of recognizing foreign antigens in the presence of self MHC molecules are retained and expanded (positive selection) for export to the periphery (lymph nodes, spleen, mucosa-associated lymphoid tissue, peripheral blood), where they become activated after encountering MHC-presented peptides (Figures 55–2 and 55–3).
Studies using murine T-cell clones have demonstrated the presence of two subsets of T helper lymphocytes (Th1 and Th2) based on the cytokines they secrete after activation. The Th1 subset characteristically produces IFN-γ, IL-2, and IL-12 and induces cell-mediated immunity by activation of macrophages, cytotoxic T cells (CTLs), and NK cells. The Th2 subset produces IL-4, IL-5, IL-6, and IL-10 (and sometimes IL-13), which induce B-cell proliferation and differentiation into antibody-secreting plasma cells. IL-10 produced by Th2 cells inhibits cytokine production by Th1 cells via the downregulation of MHC expression by APCs. Conversely, IFN-γ produced by Th1 cells inhibits the proliferation of Th2 cells (Figure 55–3). Although these subsets have been well described in vitro, the nature of the antigenic challenge that elicits a Th1 or Th2 phenotype is less clear. Extracellular bacteria typically cause the elaboration of Th2 cytokines, culminating in the production of neutralizing or opsonic antibodies. In contrast, intracellular organisms (eg, mycobacteria) elicit the production of Th1 cytokines, which lead to the activation of effector cells such as macrophages.