Cell-mediated immunity Regulation of the immune response

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Presentation transcript:

Cell-mediated immunity Regulation of the immune response Lecture VIII Cell-mediated immunity Regulation of the immune response

CTLA-4-mediated inhibition of T cells CTLA-4-mediated inhibition of T cells. T cells are activated when TCRs bind antigen displayed in the MHC on antigen-presenting cells in concert with CD28:B7-mediated costimulation. A, In the case of a weak TCR stimulus, CD28:B7 binding predominates, resulting in a net positive activating signal and IL-2 production, proliferation, and increased survival. B, In the case of a strong TCR stimulus, CTLA-4 expression is upregulated by increased transport to the cell surface from intracellular stores and decreased internalization. CTLA-4 competes with CD28 for binding of B7 molecules. Increased CTLA-4:B7 binding can result in a net negative signal, which limits IL-2 production and proliferation, and limits survival of the T cell. CTLA-4 indicates cytotoxic T-lymphocyte–associated antigen 4; IL-2, interleukin-2; MHC, major histocompatibility complex; TCR, T-cell receptor.

CTLA-4-mediated inhibition of Tregs CTLA-4-mediated inhibition of Tregs. One hypothesis of how CTLA-4 expression on Tregs can inhibit T-cell activation is depicted. Constitutive expression of CTLA-4 on Tregs can sequester or cause internalization (not depicted) of B7 molecules on antigen-presenting cells. The lack of CD28:B7-mediated costimulation leads to reduced T-cell proliferation and reduced effector functions. CTLA-4 indicates cytotoxic T-lymphocyte–associated antigen 4; MHC, major histocompatibility complex; TCR, T-cell receptor; Tregs, regulatory T cells

PD-1-mediated inhibition of T cells PD-1-mediated inhibition of T cells. T cells recognizing tumor antigens can be activated to proliferate, secrete inflammatory cytokines, and resist cell death. Prolonged TCR stimulation during an ongoing immune response can cause upregulated PD-1 expression. Tumor cells can express PD-L1 (and PD-L2, not shown) as a consequence of inflammatory cytokines and/or oncogenic signaling pathways. PD-1:PD-L1 binding inhibits TCR-mediated positive signaling, leading to reduced proliferation, reduced cytokine secretion, and reduced survival. IFN-γ indicates interferon-γ; MHC, major histocompatibility complex; PD-1, programmed death protein 1; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2; TCR, T-cell receptor.