A Clonal Culture System Demonstrates That IL-4 Induces a Subpopulation of Noncytolytic T Cells with Low CD8, Perforin, and Granzyme Expression

Abstract

Immune deviation of cytolytic T cell function, induced by type 2 cytokines like IL-4, is an attractive concept to explain failure of the immune system in some diseases. However, this concept is challenged by previous conflicting results on whether type 2 cytokine-producing CD8+ T cells are cytolytic. Therefore, we have analyzed the relationship between cytolytic activity and cytokine production among large numbers of primary CD8+ T cell clones. Single murine CD8+ T cells of naive phenotype were activated at high efficiency with immobilized Abs to CD3, CD8, and CD11a in the presence of IL-2 (neutral conditions) or IL-2, IL-4, and anti-IFN-γ Ab (type 2-polarizing conditions) for 8–9 days. Under neutral conditions, most clones produced IFN-γ without IL-4 and were cytolytic. Under type 2-polarizing conditions, most clones produced IFN-γ and IL-4 but displayed variable cytolytic activity and CD8 expression. Separation on the basis of surface CD8 levels revealed that, compared with CD8high cells from the same cultures, CD8low cells were poorly cytolytic and expressed low levels of perforin mRNA and protein and granzyme A, B, and C mRNA. A similar, smaller population of noncytolytic CD8low cells was identified among CD8+ T cells activated in mixed lymphocyte reaction with IL-4. Variable efficiency of generation of the noncytolytic cells may account for the differing results of earlier studies. We conclude that IL-4 promotes the development of a noncytolytic CD8low T cell phenotype that might be important in tumor- or pathogen-induced immune deviation.

Protection, systemic IFNγ, and antibody responses induced by an ISCOM-based vaccine against a recent equine influenza virus in its natural host

“…In humans, circulating T cells expressing low CD8 have been shown to represent a subset of highly activated CD8 T lymphocyte effectors, synthesising IFN and displaying increased cytotoxicity [34]. This is in contrast to CD8 low T lymphocytes derived from naïve CD8 + T cell cultivated in presence of IL-4, as previously described in mice [10,11]. In these studies, CD8 low T lymphocytes have been shown to be a stable subpopulation with noncytolytic activity, able to synthesise both IL-4 and IFN after antigenic stimuli.…”

Paradoxical Roles of IL-4 in Tumor Immunity

“…As early as in 1993, IL-4 was found to induce ionomycin/ phorbol myristate acetate (PMA) stimulated CD8 + T cells to differentiate into non-lytic CD4 -CD8 -T cells (34). Kienzle et al also demonstrated that culturing naïve murine CD8 + T cells in the presence of IL-4 and anti-IFNγ mAb led to the generation of CD8 low cells that were poorly cytolytic and expressed low levels of perforin and granzyme A, B and C (35,36).…”

Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus

“…degree of CD8 down-regulation was relatively modest (e.g., 2-to 4-fold) and similar to the degree of CD8 down-regulation observed in this study in the context of the HIV-1-infected thymus. It is possible that nonfunctional CD8 low peripheral T cells are also generated during the course of HIV-1 disease, perhaps through aberrant thymic selection mediated by enhanced MHC I expression on TEC or in response to increased secretion of IL-4 in the thymus and/or the periphery (41). During primary infection with HIV-1, the CD8 ϩ T cell response successfully controls viral replication and leads to the establishment of a chronic infection.…”