Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4

Abstract

T cells express T-cell antigen receptors (TCR) for the recognition of antigen in conjunction with the products of the major histocompatibility complex. They also express two key surface coreceptors, CD4 and CD8, which are involved in the interaction with their ligands. As CD4 is expressed on the early haemopoietic progenitor as well as the early thymic precursor cells, a role for CD4 in haemopoiesis and T-cell development is implicated. Thymocytes undergo a series of differentiation and selection steps to become mature CD4+8- or CD4-8+ (single positive) T cells. Studies of the role of CD4+ T cells in vivo have been based on adoptive transfer of selected or depleted lymphocytes, or in vivo treatment of thymectomized mice with monoclonal antibodies causing depletion of CD4+ T cells. In order to study the role of the CD4 molecule in the development and function of lymphocytes, we have disrupted the CD4 gene in embryonic stem cells by homologous recombination. Germ-line transmission of the mutation produces mutant mouse strains that do not express CD4 on the cell surface. In these mice, the development of CD8+ T cells and myeloid components is unaltered, indicating that expression of CD4 on progenitor cells and CD4+ CD8+ (double positive) thymocytes is not obligatory. Here we report that these mice have markedly decreased helper cell activity for antibody responses, although cytotoxic T-cell activity against viruses is in the normal range. This differential requirement for CD4+ helper T cells is important to our understanding of immune disorders including AIDS, in which CD4+ cells are reduced or absent.

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

“…The cytokine IL-7 plays a fundamental role in homeostasis of the peripheral T-cell compartment [2][3][4]. IL-7 is limiting in replete conditions and is a key determinant of the T-cell compartment size, since total T-cell numbers in mice lacking one or other CD4 1 and CD8 1 subsets are near-identical to those in mice with both subsets [5][6][7]. Conversely, genetic over-expression of IL-7 [8,9] or its administration in vivo [10] increases T-cell numbers.…”

CD4+T Cells from CD4C/HIVNefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

“…The AD10 TcR Tg mice (H-2 k ) (V␣11 and V␤3 specific for pigeon and moth cytochrome c presented by 1-E k ) were provided by Patrice Hugo and were backcrossed with CD4C/HIV Nef Tg mice which had been bred on the B10.BR background for at least seven generations and which were found to be negative for mouse mammary tumor virus types 1 and 6 by genotyping. The CD4-deficient mice were previously described (50) and were originally on a C57BL/6 background. These CD4-deficient mice were backcrossed with CD4C/HIV MutA Tg mice to generate double-mutant mice.…”

Redirecting human CD4+ T lymphocytes to the MHC class I-restricted melanoma antigen MAGE-A1 by TCR αβ gene transfer requires CD8α

“…8,9 On the other hand, the important role of CD4 + T lymphocytes in the induction and persistence of effective immunity was demonstrated in studies using CMV-specific CTL clones as well as CD4 knockout mice. [10][11][12][13][14][15] After adoptive transfer of CMV-specific CD8 + CTL to patients, which lacked CD4 + CMV-specific T lymphocytes, the CD8 + T-cell response to CMV declined, suggesting an essential role for CD4 + T-helper lymphocytes in the persistence of the transferred CD8 + CTLs. 10,11 The efficacy of the infused CD8 + CTL was improved by the coadministration of the Th1-type cytokine IL-2, supporting the notion of collaborations between CD4 and CD8 T cells.…”

“…11 Furthermore, mice deficient for CD4 were shown to be unable to maintain lymphocytic choriomeningitis virus (LCMV)-specific CD8 + CTL or clear virus following a challenge with low-dose LCMV. 12 Additionally, the induction of tumorspecific CTL against autologous MHC class II-negative effusion-associated mononuclear cell tumors was shown to be severely impaired, indicating that CD4 + T lymphocytes are essential for the induction of protective antitumor CD8 + CTL. 16 Adoptive transfer of CD4 + tumor-specific T lymphocytes may therefore be clinically relevant for effective antitumor responses.…”