Human CD4 restores normal T cell development and function in mice deficient in murine CD4.

Abstract

SummaryThe ability of a human coreceptor to function in mice was investigated by generating human CD4 (hCD4)-expressing transgenic mice on a mouse CD4-deficient (mCD4 -/-) background. From developing thymocyte to matured T lymphocyte functions, hCD4 was shown to be physiologically active. By examining the expansion and deletion of specific V/3 T cell families in mutated mice with and without hCD4, it was found that hCD4 can participate in positive and negative selection. Mature hCD4 single positive cells also were found in the periphery and they were shown to restore MHC class II-restricted alloreactive and antigen-specific T cell responses that were deficient in the mCD4 (-/-) mice. In addition, these hCD4 reconstituted mice can generate a secondary immunoglobulin G humoral response matching that of mCD4 wild-type mice. The fact that human CD4 is functional in mice and can be studied in the absence of murine CD4 should facilitate studies of human CD4 activity in general and human immunodeficiency virus 1 gp120-mediated pathogenesis in acquired immune deficiency syndrome specifically. oc//3 T cells are primarily subdivided on the basis of the CD4 or CD8 coreceptors that they express. CD8 T cells recognize MHC dass I in conjunction with cytoplasmic peptide. Upon antigen recognition, these cells deliver effector function which leads to the killing of the cell that is recognized. In this way, these cytotoxic T cells play a major role to resistance to viral infection by the elimination of vitally infected cells. CD4 T cells recognize MHC dass II in conjunction with antigenic peptide that derives from the extraceUular compartment, or from intracellular vesicles. CD4 T cells either potentiate the inflammatory response by the synthesis of the cytokines IFN-'y, TNF-c~ and/3, and so on, whereas a second subset of CD4 T cells synthesizes the cytokines such as IL-4 and IL-5, and potentiates the humoral immune response (1, 2). The coreceptors CD4 and CD8 both interact directly with their ligands MHC dass I and II, respectively. Moreover, CD4 and CD8 interact directly with the tyrosine kinase kk via binding of this enzyme to the cytoplasmic tail of these molecules (3). In a way that is not well understood at present, this interaction contributes to the delivery of the antigen-specific fig Antibodies to these molecules block T cell development and recent studies using CD4 or CD8 deficient mice show defective development of the helper and cytotoxic T cell compartments, respectively (9, 10). Positive and negative selection of thymocytes was dysfunctional when a mutant class I molecule that was unable to bind CD8 was used as a restriction element (5). Moreover, in mice that are deficient for mouse CD4, it has also been shown that the alloreactivity to MHC class II antigen and the antibody response to a T cell-dependent soluble antigen are markedly diminished (10).Despite having essentially identical functions in mice and humans, the overall homology of human CD4 (hCD4) 1 to murine CD4 (mCD4) is low (11). But upon closer inspecti...

The TCRα Locus Control Region Specifies Thymic, But Not Peripheral, Patterns of TCRα Gene Expression

“…We definitively show the expression of TCR␣ LCR-linked transgenes in cells of the B lineage. Because studies of hCD2 transgenes have shown its expression in the mouse B cell compartment (27,47), we were concerned that the ectopic B cell expression seen in our study may be an artifact of the hCD2 reporter. To address this concern, we examined the pattern of a TCR␣ LCR-linked human ␤-globin reporter fragment and still observed expression in B cells.…”

CD4 Raft Association and Signaling Regulate Molecular Clustering at the Immunological Synapse Site

“…These mutants have been previously described and exhibit normal trafficking to the cell surface as well as lck binding (16). Human CD4 molecules have been shown to be functional in mouse T cells in that they are able to rescue T cell development and function in CD4-deficient mice (19,20). These constructs were then used to infect CD4-deficient T cells, and sorted GFP-expressing cells were analyzed.…”

Developmental dissociation of T cells from B, NK, and myeloid cells revealed by MHC class II–specific chimeric immune receptors bearing TCR-ζ or FcR-γ chain signaling domains

“…The affinity of the human CD4 receptor for murine and human major histocompatibility complex class II (MHCII) is insufficient for activation of CD4/␥-expressing T cells. 1,2,[8][9][10][11] However, the consequences of such lowaffinity interactions on lymphoid development have not been examined.…”