▪ Abstract T cells play a central role in the initiation and regulation of the immune response to antigen. Both the engagement of the TCR with MHC/Ag and a second signal are needed for the complete activation of the T cell. The CD28/B7 receptor/ligand system is one of the dominant costimulatory pathways. Interruption of this signaling pathway with CD28 antagonists not only results in the suppression of the immune response, but in some cases induces antigen-specific tolerance. However, the CD28/B7 system is increasingly complex due to the identification of multiple receptors and ligands with positive and negative signaling activities. This review summarizes the state of CD28/B7 immunobiology both in vitro and in vivo; summarizes the many experiments that have led to our current understanding of the participants in this complex receptor/ligand system; and illustrates the current models for CD28/B7-mediated T cell and B cell regulation. It is our hope and expectation that this review will provoke additional ...

Cd28/b7 system of t cell costimulation

Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4

CTLA-4 can function as a negative regulator of T cell activation

The importance of the B7/CD28/CTLA-4 molecules has been established in studies of antigen-presenting cell-derived B7 and its interaction with the T cell costimulatory molecule CD28. CTLA-4, a T cell surface glycoprotein that is related to CD28, can also interact with B7-1 and B7-2. However, less is known about the function of CTLA-4, which is expressed at highest levels after activation. We have generated an antibody to CTLA-4 to investigate the consequences of engagement of this molecule in a carefully defined system using highly purified T cells. We show here that the presence of low levels of B7-2 on freshly explanted T cells can partially inhibit T cell proliferation, and this inhibition is mediated by interactions with CTLA-4. Cross-linking of CTLA-4 together with the TCR and CD28 strongly inhibits proliferation and IL-2 secretion by T cells. Finally, results show that CD28 and CTLA-4 deliver opposing signals that appear to be integrated by the T cell in determining the response to activation. These data strongly suggest that the outcome of T cell antigen receptor stimulation is regulated by CD28 costimulatory signals, as well as inhibitory signals derived from CTLA-4.

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CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.

B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: Application to autoimmune disease therapy

Antigen-specific T cell activation depends on T cell receptor-ligand interaction and costimulatory signals generated when accessory molecules bind to their ligands, such as CD28 to the B7 (also called BB1) molecule. A soluble fusion protein of human CTLA-4 (a protein homologous to CD28) and the immunoglobulin (lg) G1 Fc region (CTLA4lg) binds to human and murine B7 with high avidity and blocks T cell activation in vitro. CTLA4lg therapy blocked human pancreatic islet rejection in mice by directly affecting T cell recognition of B7+ antigen-presenting cells. In addition, CTLA4lg induced long-term, donor-specific tolerance, which may have applications to human organ transplantation.

https://science.sciencemag.org/content/sci/257/5071/789.full.pdf

Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg

Cognate recognition of antigen-presenting cells by antigen-specific T cells is critically dependent on non-cognate adhesive interactions. For instance, several studies have shown that in vivo anti-LFA-1 plus anti-ICAM-1 mAb treatment results in prolongation of allograft survival. We have developed a xenogeneic islet transplant model to investigate the role of various adhesion interactions in the xenogeneic response and study the effect of pretreating donor tissue with immunosuppressive drugs. Pancreatic islet cells were pretreated in vitro with anti-human ICAM-1 mAb, transplanted under the renal capsule of diabetic B6 mice in the absence of systemic immunosuppression and examined for long-term xenograft acceptance. The survival of human islets pretreated with anti-human ICAM-1 was significantly prolonged (MST = 53 days, with 40% of grafts surviving > 100 days). In contrast, the survival of human islets pretreated with the control antibody was similar to those of nontreated islets (MST = 7 days). A massive lymphocyte infiltrate into control xenografts was observed at 5 days post-transplant. In contrast, a lymphocyte infiltrate did not appear in the anti-ICAM-1-treated islets for at least 11 days. Only mAbs specific for the LFA-1 binding epitope of ICAM-1 were found to inhibit a mixed islet/lymphocyte reaction in vitro and block graft rejection in vivo. However, graft prolongation is not accompanied by systemic tolerance. Mice transplanted simultaneously with human islet cells treated with control Ig (left kidney) or anti-ICAM-1 (right kidney) rejected the control islets but not anti-ICAM-1-treated islets. These results suggest that the LFA-1/ICAM-1 interaction is a critical component for xenograft rejection and, more important, that pretreatment of islet tissue with anti-adhesion molecule antibodies can profoundly alter graft recognition and rejection in the absence of any systemic drug therapy. However, graft prolongation is not accompanied by systemic tolerance induction.

A Montag

Papers

Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg

Inhibition of transplant rejection by pretreatment of xenogeneic pancreatic islet cells with anti-icam-1 antibodies