Helper T cell anergy: from biochemistry to cancer pathophysiology and therapeutics

Tolerance in vivo and its in vitro counterpart, anergy, are defined as the state in which helper T lymphocytes are alive but incapable of producing IL -2 and expanding in response to optimal antigenic stimulation. Anergy is in duced when the T cell receptor (TCR) is engaged by antigen in the absence o f costimulation or IL-2. This leads to unique intracellular signaling event s that stand in contrast to those triggered by coligation of the TCR and co stimulatory receptors. Specifically, anergy is characterized by lack of act ivation of lck, ZAP 70, Ras, ERK, JNK, AP-1, and NF-AT. In contrast, anergi zing stimuli appear to activate the protein tyrosine kinase fyn, increase i ntracellular calcium levels, and activate Rap1. Moreover, anergizing TCR si gnals result in increased intracellular concentrations of the second messen ger cAMP. This second messenger upregulates the cyclin-dependent kinase (cd k) inhibitor p27(kip1), sequestering cyclin D2-cdk4, and cyclin E/cdk2 comp lexes and preventing progression of T cells through the G(1) restriction po int of the cell cycle. In contrast, costimulation through CD28 prevents p27 (kip1) accumulation by decreasing the levels of intracellular cAMP and prom otes p27(kip1) downregulation due to direct degradation of the protein via the ubiquitin-proteasome pathway. Subsequent autocrine action of IL-2 leads to further degradation of p27(kip1) and entry into S phase. Understanding the biochemical and molecular basis of T cell anergy will allow the develop ment of new assays to evaluate the immune status of patients in a variety o f clinical settings in which tolerance has an important role, including can cer, autoimmune diseases, and organ transplantation. Precise understanding of these biochemical and molecular events is necessary in order to develop novel treatment strategies against cancer. One of the mechanisms by which t umors downregulate the immune system is through the anergizing inactivation of helper T lymphocytes, resulting in the absence of T cell help to tumor- specific CTLs. Although T-cells specific for tumor associated antigens are detected in cancer patients they often are unresponsive. Reversal of the de fects that block the cell cycle progression is mandatory for clonal expansi on of tumor specific T cells during the administration of tumor vaccines. R eversal of the anergic state of tumor specific T cells is also critical for the sufficient expansion of such T cells ex vivo for adoptive immunotherap y. On the other hand, understanding the molecular mechanisms of anergy will greatly improve our ability to design novel clinical therapeutic approache s to induce antigen-specific tolerance and prevent graft rejection and graf t-versus-host disease. Such treatment approaches will allow transplantation of bone marrow and solid organs between individuals with increasing HLA di sparity and therefore expand the donor pool, enable reduction in the need f or nonspecific immunosuppression, minimize the toxicity of chemotherapy, an d reduce the risk of opportunistic infections.