The Role of Negative Costimulators During Parasitic Infections

Abstract

Activation of T lymphocytes through TCR signalling takes place within the context of numerous other cell surface proteins. To prevent unnecessary activation of T cells the immune system has developed an intricate balance between positive and negative costimulatory signals. Positive costimulatory signals determine whether antigen recognition by T cells leads to full activation or to anergy/death. In contrast, the expression of negative costimulatory molecules by T cells such as cytotoxic T lymphocyte antigen 4 (CTLA-4) mediates the regulation of an immune response and thus plays a pivotal role in the maintenance of peripheral tolerance. The new members of the CD28 family members, programmed death-1 (PD-1) and B and T lymphocyte attenuator (BTLA) are expressed more broadly on various immune cells and are also induced upon inflammation. There is increasing evidence that negative costimulators are critically involved in the regulation of immune responses against parasitic infections. The production of pro-inflammatory cytokines is often required to control parasites but the same cytokines contribute to immunopathology. Recent studies indicate that these negative costimulators are not redundant but fulfil specific functions in different tissues. This might represent a means to provoke a fine-tuning of the immune response and to define tissue specific limits of inflammation that ensure proper physiological function of the respective organ. Thus, negative costimulators represent possible drug targets since their blockade leads to an increased immune response whereas their ligation dampens T cell activation and thereby might prevent immunopathology. This review examines the role of negative costimulators during parasitic infections, and we also discuss their therapeutic potential.