TCR ζ-chain downregulation: curtailing an excessive inflammatory immune response

Abstract

The T-cell receptor (TCR) functions in antigen recognition and signal transduction, which are two crucial steps in the initiation of an antigen-specific immune response. Of the TCR subunits, the ζ-chain has an important role in receptor assembly, expression and signalling. Downregulation of the expression of the ζ-chain and impairment of T-cell function occur in T cells that have been isolated from patients with various pathologies, such as cancer, infections and autoimmune diseases. This occurs under conditions of sustained exposure to antigen and chronic inflammation, and it affects all T cells, including those not involved in triggering the specific immune response. Interferon-γ has an important role in the induction of this phenomenon by recruiting and/or activating regulatory myeloid suppressor cells (MSCs) to lymphatic organs. During chronic inflammation, these cells create an immunosuppressive environment, leading to the downregulation of ζ-chain expression by T cells and natural killer cells and affecting cell differentiation and/or proliferation, and cytokine secretion. Cumulative data indicate that downregulation of ζ-chain expression and impairment of T-cell function are normal responses of the immune system, which have evolved to attenuate T-cell function and to overcome the exacerbated activation that occurs in a developing chronic inflammatory environment. This phenomenon has a major impact on current immunotherapies, because an immunosuppressive environment might obstruct the efficacy of vaccinations and T-cell therapies. ζ-chain expression levels could be used as a prognostic marker for the presence of an immunosuppressive environment and for measuring the impact of the pathology on the immune system of the patient. If downregulation of ζ-chain expression is detected in a patient, agents that restore normal immune function must be administered before, or in conjunction with, the immunotherapy. Blockade of negative regulatory pathways might be required to potentiate the effect of any immunotherapies used.