T-cell costimulation in graftversus- host disease and graft-versus-leukemia effect - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 194

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FIGURE 10.1
Costimulation shared by conventional or effector T cells (Teffs) and regulatory T cells (Tregs). The ligands of the B7 and TNF families are expressed on antigen-
presenting cells (APCs; center) and engage the receptors of the CD28 and TNFR families expressed on Teffs (left) and Tregs (right). Some costimulatory receptors, includ-
ing CD28, ICOS, and CD30, regulate the activation/function of both types of T cells similarly. In contrast, several receptors, including 4-1BB and OX40, regulate Teffs
positively (indicated as “+”) but regulate Tregs negatively (indicated as “−”), whereas several receptors, including CTLA4, GITR, and PD-1, regulate Teffs negatively but
Tregs positively. The shapes represent CD28, B7, TNFR, or TNF family members, and the colors indicate individual molecules.
B7/CD28 superfamily
B7/CD28/CTLA4 pathway
CD28 and CTLA4 are the best-characterized receptors of the immunoglob-
ulin superfamily. The CD28 receptor is constitutively expressed on naïve
CD4 + and CD8 + T cells in mice and humans, except that a proportion of
CD8 + memory T cells are CD28 − cells in humans. CTLA4 is expressed on
activated but not resting T cells. Both CD28 and CTLA4 form homodimers
and bind the ligands B7-1 (CD80) and B7-2 (CD86). However, CTLA4 binds
to B7 ligands with much higher affinity (10- to 20-fold) than CD28, with a
preference for B7-1 [5] . B7-1 expression is inducible and can be expressed
by antigen-presenting cells (APCs) and many other cell types, includ-
ing activated T cells. While B7-2 is constitutively expressed by APCs, its
levels of expression are upregulated upon activation. Although T-cell
activation can occur with a potent TCR signal alone, CD28 costimulation is
required in most responses to antigen. Without CD28, TCR often induces
a nonresponsive, anergic state or cell death. T cells from CD28-deficient
mice show reduced proliferation in response to peptide antigens [6] . By
contrast, CTLA4 dampens T-cell responses in a manner that can protect
against the development of autoproliferative or autoimmune diseases [7] .