Signal transduction through cd4 receptors: stimulatory vs. inhibitory activity is regulated by cd4 proximity to the cd31t cell receptor

Ledbetter, Jeffrey A.; June, Carl H.; Rabinovitch, Peter S.; Grossmann, Angelika; Tsu, Theta T.; Imboden, John B.

doi:10.1002/eji.1830180406

Cited by 164 publications

(79 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Evidence for an intercellular binding of CD4 to the class II MHC has been obtained (19). On the other hand, there are several lines of evidence suggesting that CD4 may interact with the TCR or the TCR-T3 complex within the Th-cell membrane (20)(21)(22)(23)(24)(25)(26).…”

Section: Methodsmentioning

confidence: 99%

Molecular dynamics in the membranes of helper T cells.

Kupfer

Singer

1988

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We provide evidence that redistributions and interactions of integral proteins in the fluid membranes of helper T (Th) cells may play important roles in Th-cell activation. A particular monoclonal antibody, 3D3, directed to a clonotypic determinant on the T-cell receptor (TCR) of the cloned Th-cell line D10, had previously been shown to be distinctively capable of directly activating D10 cells at low concentrations. We demonstrate here by immunofluorescence experiments that it is also distinctively able itself to produce a clustering (capping) of the TCRs on the D10 cell surface. Simultaneously, by means of double-immunofluorescence experiments, we find that the 3D3-induced clustering of the TCRs distinctively produces a co-clustering of the accessory molecule CD4 with the TCR clusters, although the CD4 and TCR molecules are normally independent of one another in the D10 cell membrane. These results, and related ones previously obtained from studies of the interactions of D10 Th cells with antigen-presenting cells, are analyzed to suggest that the membrane clustering of TCRs and the induced TCR-CD4 interactions are critical to the signaling events in Th-cell activation.The direct interaction of helper T (Th) cells with specific antigen-presenting B cells (APCs) has been implicated in the proliferation and ultimate differentiation of APCs into antibody-secreting plasmacytes as well as in the proliferation of, and induction of lymphokine secretion by, Th cells. That such a direct cell-cell interaction occurs was previously inferred from the fact that a Th cell expresses on its surface a clonotypic T-cell receptor (TCR) with specific affinity for a unique ligand on the surface of an APC, a ligand consisting of a fragment of an antigen molecule attached to a molecule of the polymorphic class II major histocompatibility complex (MHC), and was supported by studies of specific binding of Th hybridoma cells to monolayers of APCs (1). That specific binary Th-APC interactions indeed occur has been demonstrated by immunofluorescence microscopy experiments with individual cell-cell couples formed between cloned Th cells and APCs (2-4), and also by specific cell-cell binding observations (5). Two phenomena were shown to identify a specific Th-APC couple and distinguish it from a nonspecific cell couple: (i) massive reorganizations of cytoplasmic organelles and of cytoskeletal proteins occur inside the Th cell (2, 3), and (ii) the TCRs become concentrated into the region of the Th cell surface that is in contact with the APC (4).In addition to the TCR, the accessory molecules CD4 and lymphocyte function-associated antigen 1 (LFA-1) on the Th cell are thought to play important roles in the Th-APC interaction (see Discussion), but the precise nature of those roles is not yet known. Of considerable interest, therefore, are the observations that both CD4 (4) and LFA-1 molecules (A.K., S. L. Swain, and S.J.S., unpublished experiments) are also clustered with the TCR into the region of the Th-cell membrane that is in contac...

show abstract

Section: Methodsmentioning

confidence: 99%

Molecular dynamics in the membranes of helper T cells.

Kupfer

Singer

1988

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Antibody crosslinking of the T-cell receptor by using anti-CD3 antibodies or cross-linking of the CD4 cell surface glycoprotein has been previously shown to result in phosphorylation and activation of p56Ick (1,47,49,51). Simultaneous cross-linking of both the T-cell receptor and the CD4 glycoprotein has been shown to enhance some parameters of T-cell activation compared with cross-linking of either CD3 or CD4 alone (29,33). Others have demonstrated an increase in p56 ck-associated PI3K activity in T cells following T-cell receptor activation (44).…”

Section: Resultsmentioning

confidence: 99%

The SH3 domain of p56lck is involved in binding to phosphatidylinositol 3'-kinase from T lymphocytes.

Vogel

Fujita

1993

Mol. Cell. Biol.

View full text Add to dashboard Cite

Many of the Src-like tyrosine kinases are thought to participate in multiprotein complexes that modulate transmembrane signalling through tyrosine phosphorylation. We have used in vitro binding studies employing bacterially expressed glutathione S-transferase-p561k fusion proteins and cell extracts to map regions on p56kk that are involved in binding to phosphatidylinositol 3'-kinase (P13K). Deletions within the SH3 domain of pS6kk abolished binding of P13K activity from T-cell lysates, whereas deletion of the SH2 domain caused only a slight reduction in the level of P13K activity bound to p56kk sequences. The binding of P13K from T-cell extracts to p56kk was not blocked by antiphosphotyrosine antibodies, but p56-kkbound P13K activity was sensitive to phosphatase treatment. The SH3 domain of p56kk also bound the majority of P13K activity from uninfected chicken embryo fibroblasts. However, a drastically different binding specificity was observed with use of extracts of Rous sarcoma virus v-src-transformed cells, in which the majority of P13K activity bound to the SH2 domain of p56k in a phosphotyrosine-dependent manner. These results suggest that are two modes of PI3K binding to p56kk, and presumably to other Src-like tyrosine kinases. In one mode, PI3K from T cells or uninfected chicken embryo fibroblasts binds predominantly to the SH3 domain of p56kk. In the other mode, involving P13K from Rous sarcoma virus-transformed cells, binding is largely phosphotyrosine dependent and requires the SH2 domain of pS6kk.The Ick gene is a member of the src family of genes, which encode a series of eight closely related protein tyrosine kinases (for a review, see reference 23?. The product of the ick gene is a 56-kDa protein (p561 ) that is expressed predominantly in cells of the lymphoid lineage, primarily T lymphocytes and lymphoid tumor cell lines (28, 30, 37).Expression of p56" has also been observed in human carcinomas of the lung and colon (50).Members of the Src family of tyrosine kinases are characterized by an NH2-terminal unique region followed by three regions that contain different degrees of homology among all members of the family (23, 42). In p561ck, Src homology region 3 (SH3) extends from amino acids 56 to 114. The SH2 domain includes amino acids 115 to 221 and the SH1, or catalytic, domain comprises most of the remainder of the C-terminal half of the protein. Recent evidence indicates that the SH2 region of Src-like kinases functions as a protein association domain that is important in the formation of multienzyme complexes that regulate signal transduction through tyrosine phosphorylation (5, 27).Several proteins have been reported to form complexes with pS6lc in T lymphocytes. The NH2-terminal unique region of p56"kk has been shown to associate with the C-terminal region of two T-cell transmembrane glycoproteins, CD4 and CD8 (3,39,40,45,48). The accessory role of CD4 and CD8 in T-cell signalling has led to the suggestion that p56"'" may participate in antigen-stimulated signal transduction events (18,36)....

show abstract

“…In vivo, the impact of CD4 and CD8 on TCR signaling was shown to be, at least in part, through binding nonpolymorphic regions of MHC class II or class I, allowing CD4 and CD8 to act as auxiliary binders to tighten the key interaction between the TCR and peptide within the binding pocket of MHC. However, a number of investigators speculated that, in addition to serving as a means to stabilize interactions, the coreceptors might participate directly in signal transduction, either by initiating unique signals or by affecting signals known to be driven by TCR engagement (13)(14)(15). Although many studies using Abs directed against either CD4 or CD8 suggested that these proteins might transduce signals, it was not until the two Pillars of Immunology papers reprinted in this issue of The Journal of Immunology (16,17) were published that a molecular basis for this action could be proposed.…”

Section: Multiple Roles Of Cd4 and Cd8 In T Cell Activationmentioning

confidence: 99%

Multiple Roles of CD4 and CD8 in T Cell Activation

Koretzky

2010

The Journal of Immunology

View full text Add to dashboard Cite

Signal transduction through cd4 receptors: stimulatory vs. inhibitory activity is regulated by cd4 proximity to the cd31t cell receptor

Cited by 164 publications

References 45 publications

Molecular dynamics in the membranes of helper T cells.

Molecular dynamics in the membranes of helper T cells.

The SH3 domain of p56lck is involved in binding to phosphatidylinositol 3'-kinase from T lymphocytes.

Multiple Roles of CD4 and CD8 in T Cell Activation

Contact Info

Product

Resources

About