Response Differences between Human CD4+ and CD8+ T-Cells during CD28 Costimulation: Implications for Immune Cell-Based Therapies and Studies Related to the Expansion of Double-Positive T-Cells during Aging

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

Jones

LaForge

et al. 2004

Costimulation of purified CD8 ؉ T lymphocytes induces de novo expression of CD4, suggesting a previously unrecognized function for this molecule in the immune response. Here, we report that the CD4 molecule plays a direct role in CD8 ؉ T cell function by modulating expression of IFN-␥ and Fas ligand, two important CD8 ؉ T cell effector molecules. CD4 expression also allows infection of CD8 cells by HIV, which results in down-regulation of the CD4 molecule and impairs the induction of IFN-␥, Fas ligand, and the cytotoxic responses of activated CD8 ؉ T cells. Thus, the CD4 molecule plays a direct role in CD8 T cell function, and infection of these cells by HIV provides an additional reservoir for the virus and also may contribute to the immunodeficiency seen in HIV disease. C D8 ϩ cytotoxic T lymphocytes (CTL) have a major role in antiviral immunity, directly killing virally infected cells and producing antiviral cytokines. Activation of these cells requires interaction of the T cell receptor complex with antigenic peptide and major histocompatibility complex (MHC) class I molecules on antigen-presenting cells (APCs) followed by a second costimulatory signal (1). After activation, there is a coordinated expression of various cell surface molecules, many of which play a direct role in cytotoxic activity. We and others have shown that costimulation of CD8 ϩ T cells from the peripheral blood results in the de novo expression of CD4, a molecule previously thought to be absent on this cell type at this stage of development (2-5). These CD8 ϩ CD4 ϩ cells express higher levels of activation molecules than do costimulated CD8 ϩ T cells lacking CD4 expression (2, 6). CD8 ϩ CD4 ϩ T cells constitute Ϸ3-5% of the human peripheral blood lymphocyte pool (7-10). Certain conditions seem to influence CD8 ϩ CD4 ϩ cell levels in humans, including infection with HIV (11), human T lymphotrophic virus-1 (12), Epstein-Barr virus (8), human herpesvirus 6 (13), and aging (10). CD8 ϩ CD4 ϩ cells also have been observed in monkeys (14-17), and in mice, rats, swine, and chickens (reviewed in ref. 18). In mice, CD8 ϩ CD4 ϩ cell levels increased after inoculation with reovirus or recombinant adenovirus (19,20). In each species, the CD8 ϩ CD4 ϩ populations usually displayed the phenotype of activated or previously activated T cells and, in the studies that assessed the composition of the CD8 dimer, were predominantly CD8␣␤ (versus CD8␣␣) cells (11,15,19). The presence of CD8 ϩ CD4 ϩ cells in normal individuals and the increased representation of these cells in individuals with disease or increased antigenic stimulation suggest a role for this cell type in immunity.The CD4 molecule has an important role in CD4 ϩ T helper (Th) cell development and response to antigen, including functioning as an adhesion molecule, regulating cellular activation and gene expression, and serving as a chemotactic receptor (21-23). Its role as the primary receptor for HIV is well known (24,25). The cytoplasmic tail of the CD4 molecule on Th cells is associated with t...

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

CD4 on CD8⁺T cells directly enhances effector function and is a target for HIV infection

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

Jones

LaForge

et al. 2004

“…Our studies suggest that CD4 is an activation marker and a chemotactic receptor on a subset of CD8 ϩ T cells and that the CD8 ϩ CD4 dim cells in human peripheral blood may be cells that are actively responding to antigen. 33,34 …”

Section: Discussionmentioning

confidence: 99%

Activation of CD8 T cells induces expression of CD4, which functions as a chemotactic receptor

LaForge

Patel

et al. 2002

Blood

IntroductionThe CD4 protein has many different functions in the development and activity of a T cell. CD4 has an important role in T-helper (Th)-cell development and response to antigen in the context of major histocompatibility complex class II (MHC II). It also serves as an adhesion molecule and a chemotactic receptor, and it has a role in cellular activation. CD4, a 58-kd transmembrane glycoprotein, is a member of the immunoglobulin family of receptors. 1 The extracellular 370-amino acid portion of CD4 is folded into 4 different domains, which are designated D1 to D4. 1 These domains are involved in a variety of interactions with other proteins, such as the T-cell receptor, MHC II,, and human immunodeficiency virus (HIV) gp120. Engagement of CD4 plays an important role in the initiation of events that lead to activation of Th cells or recruitment of those cells to sites of inflammation. The cytoplasmic tail of the CD4 protein was shown to associate noncovalently with Lck, a Src-family protein tyrosine kinase. 2,3 Cross-linking of CD4 with monoclonal antibodies (mAbs) or stimulation of CD4 by IL-16 results in Lck tyrosine phosphorylation and subsequent tyrosine phosphorylation of other cellular proteins. [4][5][6] These tyrosine phosphorylation events lead to modulation of cellular activation and functional responses. 7 CD4 expression is tightly regulated during the T-cell development process, and this control has an important role in T-cell maturation and function. The coordinate cell-surface expression of CD4 and CD8 and the subsequent down-regulation of either CD4 or CD8 are definitive markers of T-cell ontogeny. Furthermore, expression of one of these molecules on mature T cells is indicative of successful selection and commitment of these cells to either the Th or T-cytotoxic lineage. 8 However, previous ideas on the terminal differentiation of a cell into either a CD4 ϩ CD8 Ϫ Th cell or a CD4 Ϫ CD8 ϩ T-cytotoxic cell have been questioned. Several studies, including one of ours, found that activation of mature CD4 Ϫ CD8 ϩ (CD8 single-positive [SP]) T cells by costimulation 9,10 or superantigen stimulation 11 results in expression of CD4, which renders these cells susceptible to infection by HIV-1. [9][10][11] We previously found that CD45RA ϩ CD8 SP cells respond to costimulation with greater expression of CD4 than do CD45RO ϩ CD8 SP cells. 10 Thus, expression of CD4 can be modulated on T cells at more mature stages of development than was previously thought, suggesting that CD4 may be involved in mature CD8 T-cell function.The CD4 molecule was previously shown to function as a chemotactic receptor for both IL-16 and the viral surface glycoprotein HIV gp120 on CD4 ϩ Th cells. IL-16 specifically binds the D4 region, and gp120 binds the D1 region of CD4. 12,13 IL-16 is a 14-kd molecule that forms homotetramers, which are required for biologic activity. 14 This cytokine is produced by a variety of cells, including CD8 and CD4 T cells, eosinophils, mast cells, bronchial epithelial cells, synovial fibroblasts,...

“…Various disease conditions appear to affect the levels of CD8 ϩ CD4 ϩ T cells. In humans, infection with HIV, human T cell leukemia virus, Epstein-Barr virus, human herpesvirus 6, and increasing age have been linked with increased percentages of CD8 ϩ CD4 ϩ T cells in the peripheral blood (3)(4)(5)(6). In mice, increases in the CD8 ϩ CD4 ϩ population have been observed after inoculation with reovirus (7), or recombinant adenovirus (8).…”

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confidence: 99%

The CD4 molecule on CD8⁺T lymphocytes directly enhances the immune response to viral and cellular antigens

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

Whitmire

Jones

et al. 2005

CD8 ؉ T lymphocytes play a major role in cellular-mediated immune responses to foreign antigen. We have previously demonstrated that costimulation of purified human CD8 ؉ T cells induces de novo expression of the CD4 molecule and that ligation of CD4 on this cell type modulates CD8 ؉ T cell activity in vitro. Herein, we investigate how the CD4 molecule expressed on murine CD8 ؉ T cells contributes to CD8 ؉ cell responses in vivo by employing adoptive transfer of CD8 cells from CD4 knockout mice into severe combined immunodeficient (SCID) recipients. Transfer of these cells into syngeneic SCID mice resulted in a decreased immune response to infection by lymphocytic choriomeningitis virus. These decreased responses occurred even in the presence of CD4 ؉ T cells, indicating that this was truly a CD8-cell defect. Similarly, transfer of CD8 ؉ T cells incapable of expressing CD4 into allogeneic SCID mice resulted in a decreased response to alloantigens compared with that of normal CD8 ؉ T cells. Therefore, CD4 expression on CD8 T lymphocytes modulates cytotoxic T lymphocyte function and is critical in vivo for optimal cell-mediated immunity to viral and alloantigens.antiviral response ͉ CD8 ϩ T cells ͉ alloantigen response ͉ cytotoxic T lymphocytes T cell development in the thymus is characterized by the appearance and disappearance of cell-surface CD4 and CD8, which are classic markers of ontogeny. It was previously thought that after synchronous expression of CD4 and CD8, the developing thymocyte becomes CD4 or CD8 single positive, permanently turning off expression of one of these molecules. These single-positive cells are then exported to the periphery to perform their respective functions: CD4 ϩ cells serving primarily as T helper (Th) cells, and CD8 ϩ cells serving primarily as cytotoxic T lymphocytes (CTLs). Our current investigation focuses on the CD8 ϩ T cell population. CD8 ϩ T cells become activated to perform their function when they encounter a specific antigen presented in the context of MHC class I and are costimulated by one of many molecules present on antigen-presenting cells (APCs) (1). A well described series of events is triggered after activation of CD8 ϩ T cells, primarily resulting in CTLs that kill antigen-expressing target cells.In contrast to the notion that commitment to the CD4 or CD8 lineage is complete or permanent after thymopoiesis, extrathymic CD8 ϩ CD4 ϩ cells have been identified in many organisms, including humans, monkeys, mice, rats, swine, and chickens (reviewed in ref.2). Various disease conditions appear to affect the levels of CD8 ϩ CD4 ϩ T cells. In humans, infection with HIV, human T cell leukemia virus, Epstein-Barr virus, human herpesvirus 6, and increasing age have been linked with increased percentages of CD8 ϩ CD4 ϩ T cells in the peripheral blood (3-6). In mice, increases in the CD8 ϩ CD4 ϩ population have been observed after inoculation with reovirus (7), or recombinant adenovirus (8). In most cases, the rise in the percentage of CD8 ϩ CD4 ϩ cells appears to be a dir...