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Development and function of T cells, their subsets and distinctive markers
The Cantor lab investigates fundamental questions in the development of the immune response, and how it may be effectively stimulated by vaccines to fight against cancer and other diseases. Several distinct lines of research are currently underway and focus on the development and function of T cells, with special emphasis on the contribution of Qa-1-restricted CD8+ regulatory T cells (Treg) that recognize peptides associated with the murine class Ib MHC molecule Qa-1 (HLA-E in man) expressed at the surface of follicular T helper (TFH) cells.
Identification of a suppressive sublineage of CD8 T cells that prevents generation of pathogenic autoantibody production and ensures self tolerance has fundamental relevance to understanding the immune system, and may also allow more efficient development of cancer vaccines in view of the propensity of tumors to induce high levels of suppressive T cells which prevent immune destruction by the host.
While most approaches to immunotherapy have focused on the contribution of CD4+ regulatory T-cells, recent studies show that increased targeting of Qa-1+ TFH cells by CD8 Treg inhibits tumor immunity, and disruption of this inhibitory interaction enhances the protective immune response in a murine model of melanoma. Genetic disruption of CD8 Treg activity resulting in enhanced anti-tumor immunity is associated with a robust antibody response to tumor-associated antigens (TAA) that cooperate with CD8 effector T cells to constrain tumor growth. These studies suggest that the CD8+ T effector–Treg ratio in tumor lymphocyte infiltrates may represent a useful prognostic index for cancer development, and that specific depletion of CD8 Treg represents a novel and potentially effective strategy for cancer treatment.
More recently, we have found that the transcription factor Helios acts as a guardian of self-tolerance in both CD4 and CD8 regulatory lineages. Definition of Helios as a key transcriptional regulator that ensures a stable Treg phenotype and maintenance of self-tolerance in the face of inflammatory and infectious challenge represents a critical new insight into T-cell biology, and suggests novel strategies for manipulating the immune response in the context of cancer. Ongoing investigations are aimed at identification of the human homologue of CD8+ Treg for analysis of their potential contribution to anti-tumor immunity.
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