Studies of T cells in health and disease : receptor usage and cytokine expression

Abstract

T Iymphocytes are crucial components for the initiation and maintenance of an immune response. To identify and characterize different T cells and their antigen specific receptors has important bearing for the understanding of underlying mechanisms in immunopathological processes and also to allow for the design of therapeutic therapies to be used for modulation of immune responses. T cell receptor (TCR) gene expression of protein and/or RNA levels was analyzed in cancer, systemic vasculitis and human immunodeficiency virus I (HIV-I) infection as well as in peripheral blood from adults or umbilical cord blood from newborns.

Tumor-infiltrating Iymphocytes (TIL) are suggested to be enriched for cells able to specifically kill tumor cells and in vitro activated TIL are currently used in immunotherapy of cancer. We detected a biased TCR usage, with a selective usage of specific TCR variable (V) genes, in cultures of in vitro activated TIL compared to that of peripheral blood of patients with ovarian and renal carcinoma. Analysis of TCR gene expression in solid ovarian carcinoma demonstrated heterogeneous pattern with occasional skewed repertories, but this could not be distinguished from the pattern observed in healthy ovaries. A selective expression of interleukin (IL) -10, interferon-y and granulocyte-macrophage colony stimulating factor, (GM-CSF) was further detected in ovarian carcinoma. IL-10 has many immunosuppressive effects and may thus be part of the explanation of the so often observed immune unresponsiveness in cancer patients.

Among self-antigens, immunoglobulins and in particular idiotypes are of special interest as potential targets for immune reactions to self. Frequent, and sometimes dramatic, clonal expansions of CD8+ T cells populations carrying a single V-a or ß gene were detected in patients with B-malignancies. However, no specific interferon- y release of the expanded subset in response to the autologous monoclonal immunoglobulin could be observed. Similar expansion, but in the CD4+ subset, was noted in patients with vasculitis. A recurrent motif in TCRBV8+ CD4+ T cells of HLA-DRB1*0401 positive patients suggested that these unrelated patients may have been exposed to, and elicited an immune response against, a common antigen.

TCR expansions were also detected at a higher frequency in infected compared to uninfected children born to HIV-I infected mothers. This demonstrated that acute viral infection can induce extensive expansion in T cell populations bearing single Va or Vß gene products in infants. Finally, the TCR CDR3 region length variation is highly restricted in peripheral CD8+ T cells which argues for dramatically different conditions for shaping and maintaining the peripheral TCR repertoire in CD4+ and CD8+ T cells. Collectively these studies demonstrate that oligoclonal expansions frequently occur in the diseases studied, but that they are also present in healthy individuals. Their precise functional role(s), however, remains to be established.