Key roles of T cells are to respond to and eliminate cells bearing foreign antigens and to ignore cells expressing self-antigens. To respond to foreign antigens, stimulating cells must deliver an activating co-stimulating signal in addition to TCR ligation. To avoid responding to cells bearing self-antigens, T cells must also maintain immune tolerance. Central T-cell tolerance is maintained by autoreactive T-cell deletion in the thymus, while peripheral tolerance is either by cell apoptosis or anergy (cell intrinsic mechanisms), or maintained by extrinsic mechanism suppression by immune modulating cells such as regulatory T cells (Treg) (see section below, “Mechanisms of Immune Dysregulation in Autoimmune Disease”). Thus, T-cell activation is an integral component of the adaptive immune response to pathogens as well as to tumor neoantigens.

Two stimulatory signals are required for T-cell activation. One T-cell signal is delivered by antigen peptide presented in the context of MHC. However, in the absence of a co-stimulating signal, the T cell will not be activated by peptide MHC alone but rather will become anergic or unresponsive. A second co-stimulatory signal is needed for T-cell activation, resulting in cytoskeletal remodeling, production of cytokines, and cell survival and differentiation. In addition to the TCR/CD3 complex, T cells express a complex array of co-stimulatory as well as inhibitory molecules that bind to their respective receptors on the surface of antigen-presenting cells (APCs) and orchestrate both initiation and control of T-cell activation to maintain immune homeostasis (Fig. 1). Of these, CD28, cytotoxic T lymphocyte antigen 4 (CTLA-4), and programmed cell death protein 1 (PD-1) and their ligands were among the first to be recognized to be central to control of T-cell activation.

Fig1. Regulatory stimulating or inhibiting molecules on T cells or antigen-presenting cells (APCs), tumor cells, or other cells.

The CD28 molecule is a member of the immunoglobulin (Ig) super family and is the original member of a subfamily of co-stimulatory or inhibitory molecules on the surface of T cells that includes CTLA-4, inducible T-cell costimulator (ICOS), PD-1, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and B- and T-cell attenuator (BTLA) (Fig. 1). CD28 stimulates intracellular signaling through AKT and PI3 kinase, resulting in induction of NF-κB, AP-1, and NFAT, which are all critical for T-cell activation and differentiation. CTLA-4 and PD-1 are CD28 subfamily members that control T-cell activation by inhibiting the stimulating activity of CD28 and other T-cell co-stimulatory molecules.

CTLA-4 is a key negative regulator of T-cell activation that down modulates the T-cell response to antigen by interaction with its ligands, B7-1 and B7-2, to control unchecked T-cell proliferation. CTLA-4 is upregulated following TCR engagement with MHC/peptide, thus dampening TCR signaling by competing with CD28 binding to B7 ligands (B7-1 [CD80] and B7-2 [CD86]) on APCs by virtue of higher affinity of CTLA-4 for B7 ligands. In this manner, T cells respond to foreign antigen but are prevented from damaging host tissues due to overexuberant responses (Fig.2A). CTLA-4 thus mediates its dampening effect on T-cell activation by competing with T-cell CD28 binding to B7 receptors, as well as through the suppressive effect of CTLA-4-positive Tregs. The human CTLA4 gene is just one of several genes in which monogenetic mutations are associated with decreased Treg function and autoimmune syndromes (Table 1).

Fig2. Molecular mechanisms of CTLA-4 and PD-1 attenuation of T-cell activation and schematic of the molecular mechanisms of action of CTLA-4 and PD-1 blockade. A. Schematic of the molecular interactions and downstream signaling induced by ligation of CTLA-4 and PD-1 by their respective ligands. The possibility of additional downstream cell-intrinsic signaling mechanisms is highlighted for both CTLA-4 and PD-1. B. The stepwise progression of T-cell activation, attenuation by normal regulatory mechanisms, and release of such negative regulation by therapeutic intervention using anti-CTLA-4 or anti-PD-1 antibodies is outlined. (Reprinted from Cancer Discovery, 2018,8/9, 1069–1086, SC Wei et al: Fundamental Mechanisms of Immune Checkpoint Blockade Therapy, with permission from AACR.)

Table1. Monogenetic Mutations That Lead to Immune Dysregulation and Autoimmunity

PD-1 is also a major inhibitory molecule of T-cell activation by interaction with its ligands PD-L1 and PD-L2 on APCs (Fig. 361-1). While initially thought to be a cell death receptor, PD-1 is expressed upon activation of T and B cells and is also a marker of T follicular helper CD4+ T cells in B-cell germinal centers. PD-1 acts to dampen T-cell activation by dephosphorylation of CD28 via the Src homology region 2–containing protein tyrosine phosphatase 2 (SHP2).

Although a marker of immune cell activation, PD-1 is also a marker for exhausted T cells. T-cell exhaustion is an important mechanism of maintaining immune homeostasis and preventing host tissue T-cell damage, but also leads to immune dysfunction in the setting of chronic antigenic stimulation such as occurs in chronic viral diseases (HIV-1, hepatitis C) and in cancer. Chronic viral diseases and tumors lead to transcriptional and metabolic signatures that define the exhausted T-cell state. T-cell exhaustion has been a major roadblock to overcome for successful cancer immunotherapy.

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علماء يبتكرون "آلية" تتوقع موعد ظهور أعراض الزهايمر

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رصد "القرش النائم" في أحد أقسى الأماكن على وجه الأرض

أسماك أعماق البحر تكشف نظاما بصريا يتجاوز "المألوف"

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Checkpoint Inhibition Therapy for Cancer

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Immunotherapy

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Cellular interactions in regulation of normal immune responses

Markers of Granulocytic Maturation

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Monocytopoiesis

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Transcription Factors Regulating Myeloid Differentiation and Myeloid-Specific Gene Expression

Cytokine Regulation of Myeloid Proliferation and Differentiation