CD4 Dependence of Activation Threshold and TCR Signalling in Mouse T Lymphocytes

Abstract

The effect of CD4 expression on the activation threshold of mouse T lymphocytes has been analysed. To do this, the authors studied the response to antigen and other T cell receptor (TCR) ligands in a series of CD4 ¹ mutants obtained from the SR.D10 clone. This non-tumour clone spontaneously arose from the Th2 clone D10.G4.1, and characteristically shows a low threshold for antigen activation as well as reactivity to syngeneic antigen presenting cells (APC). Although SR.D10 CD4¹ mutant cells can be stimulated by antigen, they need higher antigen concentration or more APC than SR.D10 or CD4 transfectants to yield optimal antigen responses. Furthermore, CD4¹ clones are not activated by syngeneic APC or by clonotypic antibodies. These effects do not correlate with changes in the expression of cell surface molecules implicated in antigen recognition, like TCR/CD3, CD2, LFA-1, or CD45, or with lower p56 lck or p59 fyn activity in the mutant cells. Since inhibition experiments using anti-CD4 antibodies have previously shown that activation of the CD4 + T cell clone D10.G4.1 by antigen or alloantigens is largely dependent on CD4, our results indicate that activation by antigen-plus self MHC may become CD4-independent if the activation threshold is lowered enough, e.g. in cells like SR.D10. Expression of CD4 further lowers the activation threshold of the cells, allowing the detection of low-affinity TCR reactivities like those directed at self MHC. Moreover, by using anti-TCR/CD3 antibodies, the authors have confirmed the importance of CD4-associated tyrosine kinase activity in early TCR/CD3 signalling in this Th2 cell line, as (1) upon TCR/CD3 ligation, tyrosine phosphorylation is detected only in those CD3 chains co-precipitating with CD4; and (2) CD4 expression is needed for efficient early tyrosine phosphorylation and detectable p56 lck -TCR co-precipitation.

Identification of a Type 1 Diabetes‐Associated CD4 Promoter Haplotype with High Constitutive Activity

“…The CD4 receptor expressed on mature Th cells colocalizes with the T-cell receptor (TCR) and major histocompatibility complex (MHC) class II molecules [3] and interacts with nonantigen-binding regions on the MHC class II molecule in antigen recognition [4]. Inhibition of CD4-MHC class II interaction severely impairs the T-cell response to antigen exposure [5], and low CD4 cell-surface expression on Th lymphocytes results in impaired TCR response to low-level antigenic stimulation [6]. The CD4 promoter seems to be the major regulatory region for CD4 transcription in the mature Th cell [7][8][9].…”

Variability of CD3 membrane expression and T cell activation capacity

“…The binding is strengthened by coreceptors, such as, CD4 or CD8 (7)(8)(9). Signal transduction is carried through CD3 that is physically associated to the TCR (10).…”

Association of CD4 enhancer gene polymorphisms with rheumatoid arthritis in Egyptian female patients

“…Also, they recognize antigen on target cells in association with class II major histocompatibility complex (MHC) molecules and interact directly with it on the surface of the antigen-presenting cell using its extracellular domain [24]. Inhibition of CD4-MHC class II interaction severely impairs the T-cell response to antigen exposure [25], and low CD4 cell-surface expression on Th lymphocytes results in impaired TCR response to low-level antigenic stimulation [9]. So, the genetic regulation of the CD4?…”

“…T cells [8]. Inhibition of CD4-MHC class II interaction severely impairs the response of T cells to antigen exposure, and low CD4 cellsurface expression on Th lymphocytes results in impaired TCR response to low-level antigenic stimulation [9].…”