Interaction between CD4 and class II MHC molecules mediates cell adhesion

Doyle, Carolyn A.; Strominger, Jack L.

doi:10.1038/330256a0

Cited by 776 publications

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“…The CD4 molecule enlarges the overall affinity of the TCR with its antigenic peptide-HLA complex through binding to the b2 domain of the HLA class II molecule. 30 It has been proposed that the dependency on CD4 is determined by the number of antigenic peptide-HLA complexes on the target cell surface. 31 The TCR requires a critical number of antigenic peptide-HLA complexes on the target cell surface for CD4-independent recognition.…”

Section: Discussionmentioning

confidence: 99%

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

et al. 2005

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Both cytotoxic T cells and helper T cells are important in immune responses against pathogens and malignant cells.In hematological malignancies which express HLA class II molecules, immunotherapy may be directed to HLA class II restricted antigens. We investigated whether it is possible to engineer HLA class II restricted T cells with both antigenspecific cytolytic activity and the capacity to produce high amounts of cytokines. CD4 + and CD8 + peripheral-bloodderived T cells were retrovirally transduced with the HLA class II restricted minor histocompatibility antigen dead box RNA helicase Y (DBY)-specific TCR. The TCR-transduced CD4 + T cells exerted DBY-specific cytolytic activity, produced Th0, Th1, or Th2 cytokines, and proliferated upon DBY-specific stimulation. TCR-transduced CD8 + T cells exerted cytolytic activity which equaled the level of cytolytic activity of the TCR-transferred CD4 + T cells. Cotransfer of CD4 enhanced the cytolytic activity of the TCR-transduced CD8 + T cells, but introduction of CD4 was not sufficient to generate DBY-specific CD8 + T cells with the capacity to produce high amounts of cytokines. In this study, we demonstrated the feasibility to engineer T cells with antigen-specific cytolytic activity, as well as the ability to produce significant amounts of cytokines, by TCR transfer to CD4 + T cells. Gene Therapy (2005) IntroductionPatients relapsing from leukemia after allogeneic stem cell transplantation can successfully be treated by donor lymphocyte infusions (DLI), due to the graft-versusleukemia (GVL) response of the donor-derived T cells. [1][2][3][4] However, DLI is also associated with graft-versus-hostdisease (GVHD). Several studies have illustrated that depletion of CD8 + T cells from the DLI may preserve the beneficial GVL reactivity without the induction of GVHD, indicating that the CD4 + T lymphocytes may play an essential role in the antileukemic reactivity. [5][6][7][8][9][10] The mechanism by which the CD4 + T cells contribute to the GVL response is, however, not known. CD4 + T cells have been suggested to elicit the antileukemic response via the induction of minor histocompatibility antigen (mHag)-specific CD8 + T cells. 5 In addition, mHag-specific CD4 + T-helper cells have been reported to mature dendritic cells and enhance the expansion of mHag-specific cytotoxic T lymphocytes in vitro. 11 Alternatively, we have demonstrated that CD4 + T cells are capable of exerting direct cytolytic activity against leukemic cells. [12][13][14] Cellular immunotherapeutic approaches based on the adoptive transfer of T lymphocytes may require large cell numbers. Large numbers of T cells with a defined antigen specificity can be acquired by retroviral transfer of the T-cell receptor to peripheral-blood-derived T lymphocytes. Until now, the application of retroviral transfer of TCRs has mainly been limited to the transfer of HLA class I restricted TCRs. [15][16][17][18][19][20] However, the specificity of HLA class II restricted T lymphocytes can also be transferred to other T c...

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Section: Discussionmentioning

confidence: 99%

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

et al. 2005

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“…CD4 participates in antigen recognition by binding to nonpolymorphic regions of class II MHC molecules, while the T-cell antigen receptor recognizes a specific peptide antigen that is bound by the MHC molecule (7). The CD4-MHC interaction serves to increase the avidity of the T cell to the antigenpresenting cell but also induces an intracellular signaling event through the CD4-associated tyrosine kinase, p561ck (8,59). Therefore, CD4 plays a critical role in the antigen recognition required for T-cell activation and helper T-cell functions.…”

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confidence: 99%

Elf-1 binds to a critical element in a second CD4 enhancer.

Wurster¹,

Siu²,

Leiden³

et al. 1994

Mol. Cell. Biol.

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The coordinated expression of CD4 and CD8 during T-cell development is tightly coupled with the maturation state of the T cell. Additionally, the mutually exclusive expression of these receptors in mature T cells is representative of the functional T-cell subclasses (CD4+ helper T cells versus CD8+ cytotoxic T cells). We have studied the regulation CD4 gene transcription during T-cell development in an attempt to gain an understanding of the molecular mechanisms involved in T-cell development and differentiation. Here we present the identification of a second transcriptional enhancer in the murine CD4 locus 24 kb upstream of the CD4 promoter. This enhancer is active in mature T cells and is especially active in CD4+ helper T cells. A number of nuclear proteins bind to elements in the minimal CD4 enhancer that includes consensus sites for AP-1, Spl, Gata, and Ets transcription factor families. We find that the Ets consensus site is crucial for enhancer activity and that the recently identified Ets factor, Elf-i, which is expressed at high levels in T cells and involved in the regulation of several other T-cell-specific genes, is a dominant protein in T-cell nuclear extracts that binds to this site.T-cell development involves the differentiation of functionally immature pre-T cells into mature, antigen-reactive effector cells (reviewed in reference 61). This process includes selection events in which the maturing T-cell population is depleted of self-reactive clones and enriched for those that can recognize foreign peptides bound by self-major histocompatibility complex (MHC). The development and selection of T-cell precursors occur in the thymus and are characterized by a coordinated expression of tissue-specific genes. Some of these genes encode cell surface molecules that directly promote T-cell differentiation and selection events. Understanding the molecular mechanisms responsible for the expression of these T-cellspecific genes is a window on the process of T-cell development.The CD4 glycoprotein is one of the surface molecules that is important as a receptor in the development and function of T cells (reviewed in references 39 and 46). In mature antigenspecific T cells, CD4 is expressed only on cells that have a T-cell receptor (TCR) specific for antigen associated with class II MHC molecules, while CD8, a cell surface protein functionally similar to CD4, is expressed only on T cells that recognize antigen bound to MHC class I molecules (56). The mutually exclusive expression of CD4 and CD8 on mature T cells also corresponds to T-cell function; CD4 is expressed primarily on helper T cells, while CD8 is expressed on cytotoxic T cells. CD4 participates in antigen recognition by binding to nonpolymorphic regions of class II MHC molecules, while the T-cell antigen receptor recognizes a specific peptide antigen that is bound by the MHC molecule (7). The CD4-MHC interaction serves to increase the avidity of the T cell to the antigenpresenting cell but also induces an intracellular signaling event through the CD4-...

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“…Generally, TCRs bind to the peptide/MHC complexes with lower affinity than Ab/Ag interactions (5)(6)(7). One function of CD4 and CD8 is to enhance the overall affinity of the complex through binding to the ␤ 2 domain of MHC class II molecules and the ␣ 3 domain of MHC class I molecules, respectively (8,9). CD4 and CD8 also provide signal transduction by association of their cytoplasmic domains with the tyrosine kinase Lck (10).…”

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confidence: 99%

CD8-Independent Tumor Cell Recognition Is a Property of the T Cell Receptor and Not the T Cell

Roszkowski

Rubinstein

et al. 2003

The Journal of Immunology

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The CD8 coreceptor enhances T cell function by stabilizing the TCR/peptide/MHC complex and/or increasing T cell avidity via interactions with the intracellular kinases Lck and LAT. We previously reported a CD4+ T cell (TIL 1383I), which recognizes the tumor-associated Ag tyrosinase in the context of HLA-A2. To determine whether CD8 independent tumor cell recognition is a property of the TCR, we used retroviral transduction to express the TIL 1383I TCR in the CD8− murine lymphoma, 58 α−/β−. Immunofluorescent staining of TCR-transduced cells with human TCR Vβ subfamily-specific and mouse CD3-specific Abs confirmed surface expression of the transferred TCR and coexpression of mouse CD3. Transduced effector cells secreted significant amounts of IL-2 following Ag presentation by tyrosinase peptide-pulsed T2 cells as well as stimulation with HLA-A2+ melanoma lines compared with T2 cells alone or HLA-A2− melanoma cells. Further analysis of TCR-transduced clones demonstrated a correlation between T cell avidity and cell surface expression of the TCR. Therefore, the TIL 1383I TCR has sufficient affinity to mediate recognition of the physiologic levels of Ag expressed by tumor cells in the absence of CD8 expression.

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Interaction between CD4 and class II MHC molecules mediates cell adhesion

Cited by 776 publications

References 0 publications

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

Elf-1 binds to a critical element in a second CD4 enhancer.

CD8-Independent Tumor Cell Recognition Is a Property of the T Cell Receptor and Not the T Cell

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