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 complex1,2. They also express two key surface coreceptors, CD4 and CDS, which are involved in the interaction with their ligands3,4. As CD4 is expressed on the early haemopoietic progenitor5 as well as the early thymic precursor cells6, a role for CD4 in haemopoiesis and T-cell development is implicated. Thymocytes undergo a series of differentiation7 and selection steps8,9 to become mature CD4+8- or CD4-8+ (single positive) T cells10,11. 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 cells12-14. 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 cells15-16 by homologous recombination17-18. Germ-line transmission19-20 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. © 1991 Nature Publishing Group.