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

Abstract

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,...

Cutting Edge: IL-16/CD4 Preferentially Induces Th1 Cell Migration: Requirement of CCR5

“…Recent studies have suggested that IL-16 may signal through an alternative receptor in cells from the monocytoid lineage, as CD4 null epidermal dendritic cells and monocytes obtained from CD4 null mice are responsive to IL-16 (9,10). In T cells, however, the data indicate a requirement of CD4 expression for induction of a cellular response to IL-16 stimulation (3,11,12). Although CD4 is required, it has not been established whether all CD4 ϩ T cells are responsive to IL-16 stimulation or whether there is a preferential subset effect.…”

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

“…We have previously determined that CD4 can function as a chemotactic receptor on activated human CD8 ϩ T cells, allowing them to migrate in response to IL-16 (16). Furthermore, we have recently determined that CD4 can directly influence human CD8 T cell function in vitro (9).…”

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.…”

“…Since blocking of the CD4 receptor in the CD4 dim CD8 + TCC did not alter the response to the peptide, and since CD4 is known to serve as a receptor for soluble IL-16 33 , we expect that co-expression of CD4 is primarily serving a role in chemotactic recruitment of CD4 dim CD8 + T cells to the site of inflammation in the cerebellum. 37,38 Our data provide novel information on host-pathogen interactions during CNS infection with JCV and illustrate alongside with the recently described antibody "recognition holes" for JCV variants in natalizumab-associated PML 39 …”

“…Detailed characterization of the CSF-derived T cell infiltrate revealed the presence of CD4 + T cells, CD8 + T cells and a subpopulation of CD4 dim CD8 + T cells which have been reported to represent activated CD8 + T cells 33 (Fig. 2A).…”