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Transcriptional

-> activation of several genes

FIGURE 10-12

Activation of the small G protein, Ras. Signals from the T-cell receptor result in activation of Ras via the action of specific guanine nucleotide exchange factors (GEFs) that catalyze the exchange of GDP for GTP. Active Ras causes a cascade of reactions that result in the increased production of the transcription factor Fos. Following their phosphorylation, Fos and Jun dimerize to yield the transcription factor AP-1. Note that all these pathways have important effects other than the specific examples shown in the figure.

CD28 delivers a positive co-stimulatory signal to the T cell; signaling through CTLA-4 is inhibitory and down-regulates the activation of the T cell. CD28 is expressed by both resting and activated T cells, but CTLA-4 is virtually undetectable on resting cells. Typically, engagement of the TCR causes the induction of CTLA-4 expression, and CTLA-4 is readily de-

CD28 is expressed by both resting and activated T cells

CD28 is expressed by both resting and activated T cells

CTLA-4 is expressed on activated T cells

Both B7 molecules are expressed on dendritic cells, activated macrophages, and activated B cells

CTLA-4 is expressed on activated T cells

Both B7 molecules are expressed on dendritic cells, activated macrophages, and activated B cells

FIGURE 10-13

TH-cell activation requires a co-stimulatory signal provided by antigen-presenting cells (APCs). Interaction of B7 family members on APCs with CD28 delivers the co-stimulatory signal. Engagement of the closely related CTLA-4 molecule with B7 produces an inhibitory signal. All of these molecules contain at least one im-munoglobulin-like domain and thus belong to the immunoglobulin superfamily. [Adapted from P. S. Linsley and J. A. Ledbetter, 1993, Annu. Rev. Immunol. 11:191.]

tectable within 24 hours of stimulation, with maximal expression within 2 or 3 days post-stimulation. Even though the peak surface levels of CTLA-4 are lower than those of CD28, it still competes favorably for B7 molecules because it has a significantly higher avidity for these molecules than CD28 does. Interestingly, the level of CTLA-4 expression is increased by CD28-generated co-stimulatory signals. This provides regulatory braking via CTLA-4 in proportion to the acceleration received from CD28. Some of the importance of CTLA-4 in the regulation of lymphocyte activation and proliferation is revealed by experiments with CTLA-4 knockout mice. T cells in these mice proliferate massively, which leads to lymphadenopathy (greatly enlarged lymph nodes), splenomegaly (enlarged spleen), and death at 3 to 4 weeks after birth. Clearly, the production of inhibitory signals by engagement of CTLA-4 is important in lymphocyte home-ostasis.

CTLA-4 can effectively block CD28 co-stimulation by competitive inhibition at the B7 binding site, an ability that holds promise for clinical use in autoimmune diseases and transplantation. As shown in Figure 10-14, an ingeniously engineered chimeric molecule has been designed to explore the therapeutic potential of CTLA-4. The Fc portion of human IgG has been fused to the B7-binding domain of CTLA-4 to produce a chimeric molecule called CTLA-4Ig. The human Fc region endows the molecule with a longer half-life in the body and the presence of B7 binding domains

] CTLA-4 binding domain

IgG Fc

(b) B7 blockade by CTLA-4Ig

T cell

(b) B7 blockade by CTLA-4Ig

T cell

CD28 B7

FIGURE 10-14

CD28 B7

FIGURE 10-14

CTLA-4Ig, a chimeric suppressor of co-stimulation.

(a) CTLA-4Ig, a genetically engineered molecule in which the Fc portion of human IgG is joined to the B7-binding domain of CTLA-4.

(b) CTLA-4Ig blocks costimulation by binding to B7 on antigen presenting cells and preventing the binding of CD28, a major co-stimulatory molecule of T cells.

allows it to bind to B7. A promising clinical trial of CTLA-4 has been conducted in patients with psoriasis vulgaris, a T-cell-mediated autoimmune inflammatory skin disease. During the course of this trial, forty-three patients received four doses of CTLA-4Ig, and 46% of this group experienced a 50% or greater sustained improvement in their skin condition. Further studies of the utility of CTLA-4Ig are also being pursued in other areas.

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