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

Abstract

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...

Potent HIV-specific responses are enriched in a unique subset of CD8+ T cells that coexpresses CD4 on its surface

“…Adoptive transfer of CD8 ϩ T cells from CD4-knockout mice to LCMV-infected mice also results in diminished immune responses. 11 These studies highlight a biologic role for CD4 on CD8 ϩ T cells in the enhancement of immunologic responses to viral infections. The exact mechanism by which CD4 exerts this heightened antiviral response on CD8 ϩ T cells is not clear.…”

“…Despite significant compelling evidence for the existence of CD4 dim CD8 bright T cells and their potential role in antiviral immune responses, 5,10,11 this population is often neglected in the analysis of antiviral CTL responses. CD4 dim CD8 bright T cells are either gated out from conventional flow cytometric analyses or grouped together with CD4 Ϫ CD8 ϩ T cells without identification or recognition of their contribution to the overall CD8 ϩ T-cell antiviral response.…”

“…4 Others have shown that CD4 expression on CD8 ϩ T cells enhances their IFN␥ and Fas ligand expression, 10 whereas, inversely, lack of CD4 expression on CD8 ϩ T cells from CD4-knockout mice leads to decreased CD8 ϩ T-cell responses against lymphocytic choriomeningitis virus (LCMV). 11 The contribution of CD4 dim CD8 bright T cells to anti-HIV immunity, however, is not clear.…”

“…In HIV infection, loss or dysregulation of CD8 ϩ T cells is correlated with disease progression. [1][2][3] Although expression of CD8 or CD4 on mature T cells is thought to be mutually exclusive, defining cytotoxic and helper cells, respectively, considerable evidence from our laboratory [4][5][6] and others [7][8][9][10][11][12] has shown that CD4 is coexpressed on a subset of CD8 ϩ T cells. In the periphery, CD4-expressing CD8 ϩ T cells constitute 3% to 5% of CD8 ϩ T cells and 1% to 3% of lymphocytes.…”

Mechanisms of immune escape in central nervous system infection with neurotropic JC virus variant

“…The upregulation of CD4 on CD8 + T cells can be induced by strong activation and has been shown to be involved in interacting with HLA-class II, IL-16-induced chemotaxis and enhanced effector functions. 25,33 Functional studies with one of the prominent brain-derived CD4 dim CD8 + TCCs revealed CD8-dependent recognition of a LTAg epitope with high affinity, Tc1 profile and cytotoxic potential.…”