Inhibitory receptors for HLA class I molecules on cytolytic T lymphocytes. Functional relevance and implications for anti-tumor immune responses.

Abstract

In recent years, the molecular mechanism by which natural killer cells lyze, or fail to lyze, different target cells has been elucidated. Natural killer cells express receptors which recognize MHC class I molecules on target cells. This interaction leads to inhibition of cytolytic activity, thus preventing lysis of target cells. The receptors belong to two distinct molecular types: (1) the lg superfamily which includes receptors (p58.1, p58.2, p70, and p140) which recognize specific HLA allotypes; (2) CD94 molecules which display a broad specificity for HLA class I molecules. Recently, a subset of cytolytic T lymphocytes has been shown to express the various natural killer cell receptors. Such T cells are detectable in peripheral blood, spleen, tonsils, and lymph nodes, but not in the thymus and cord blood. In some instances, two or more natural killer receptors can be coexpressed at the single cell level. Surface marker analysis has revealed that natural killer cell receptor-positive T cells always express a memory phenotype. Moreover, they are characterized by a skewed T cell receptor V beta repertoire. Further analysis of the T cell receptor VDI sequences revealed that natural killer cell receptor-positive, CD3-positive cells isolated from a given individual are oligoclonal or monoclonal in nature. Crosslinking of natural killer receptors leads to inhibition of different T cell functions, including non-specific lysis of appropriate HLA class I-negative target cells, T cell receptor mediated cytotoxicity, and cytokine production. The inhibitory effect on T cell receptor-mediated function has important implications. Thus, the expression of natural killer cell receptors as a consequence of chronic antigen stimulation may result in functional impairment of specific cytolytic T lymphocytes. Preliminary data indicate that this phenomenon may occur in tumor or virally infected patients. Remarkably, various patients with large granular lymphocyte expansions characterized by a CD3/ natural killer receptor-positive phenotype had chronic viral infections. The fact that antigen-specific cytolytic T lymphocytes may simultaneously express T cell and natural killer cell receptors, both recognizing HLA class I molecules but mediating opposite signals, offers new perspectives in our appreciation of the regulation of T cell responses and offers new clues for understanding the immunopathological events involved in certain diseases.