T Cell Cosignaling Molecules in Transplantation

Abstract

The ultimate outcome of alloreactivity vs. tolerance following transplantation is potently influenced by the constellation of cosignaling molecules expressed by immune cells during priming with alloantigen, and the net sum of costimulatory and coinhibitory signals transmitted via ligation of these molecules. Intense investigation over the last two decades has yielded a detailed understanding of the kinetics, cellular distribution, and intracellular signaling networks of cosignaling molecules such as the CD28, TNF and TIM families of receptors in alloimmunity. More recent work has better defined the cellular and molecular mechanisms by which engagement of cosignaling networks serve to either dampen or augment alloimmunity. These findings will likely aid in the rational development of novel immunomodulatory strategies to prolong graft survival and improve outcomes following transplantation.

An update on potentials and promises of T cell co‐signaling molecules in transplantation

“…This evidence is assuring the importance of co‐signaling molecules in the modulation of various aspects of immune responses. The mentioned qualification along with numerous evidence on dysregulation of immunoregulatory pathways during allotransplantation (Ford, ), confirms the potential of immunoregulatory molecules to serve as promising targets for tolerance induction in the case of allografts. Many of these co‐signaling molecules have key physiologic roles in immunological events such as T cell priming, clonal expansion, effector cell differentiation, immune response homeostasis, and peripheral tolerance.…”

Memory T‐cell exhaustion and tolerance in transplantation

“…38,115,116 TIGIT, while well studied in cancer and HIV immunology, is less studied in the setting of transplantation. 38,115,116 TIGIT, while well studied in cancer and HIV immunology, is less studied in the setting of transplantation.…”

Transplantation tolerance after allograft rejection

“…As a result of increased T cell receptor nanoclustering, memory T cells have a lower threshold for activation and respond to antigen more rapidly [1,2], divide after a shorter lag time, exhibit increased numbers of cell divisions coupled with lower loss rates, and more quickly elaborate effector functions [3,4]. In addition to increased signaling through the TCR, memory T cells express a higher level and broader array of co-stimulatory molecules including ICOS, CD30, TNFR4 (OX40) and TNFR9 (4-1BB) [5,6] that enhance TCR signaling, and that regulate effector function and survival. Sensitized recipients harbor higher frequencies of antigen-specific T cells and potentially, circulating antibodies, which also contributes to more vigorous T cell responses in vivo, and altered sensitivity to immunosuppression (Fig 1) [5,7,8].…”

“…In addition to increased signaling through the TCR, memory T cells express a higher level and broader array of co-stimulatory molecules including ICOS, CD30, TNFR4 (OX40) and TNFR9 (4-1BB) [5,6] that enhance TCR signaling, and that regulate effector function and survival. Sensitized recipients harbor higher frequencies of antigen-specific T cells and potentially, circulating antibodies, which also contributes to more vigorous T cell responses in vivo, and altered sensitivity to immunosuppression (Fig 1) [5,7,8]. …”