Enhanced expression of CTLA-4 (CD152) on CD4+ T cells in HIV infection

Abstract

SUMMARYCTLA-4 (CD152) is a surface molecule of activated T cells with sequence homology to CD28. Both molecules bind to the same ligands, B7.1 (CD80) and B7.2 (CD86) but have antagonistic functions. While CD28 is an important costimulator, CTLA-4 has an essential inhibitory function in maintaining the homeostasis of the immune system. Down-regulation of CD28 predominantly on CD8þ T cells has been described in HIV infection, but analysis of CTLA-4 is complicated by its low expression levels. Here we have used potent signal enhancement to study CTLA-4 on peripheral blood mononuclear cells (PBMC) during HIV infection. CTLA-4 was expressed only on T cells. Expression levels were significantly increased selectively on CD4 þ T cells during all stages of HIV infection, while CTLA-4 expression on CD8 þ T cells was always low. In contrast, after stimulation with the mitogen phytohaemagglutinin (PHA), CTLA-4 levels were strongly increased on T cells from controls but in T cells from HIV patients this response was severely impaired. Our data suggest that in HIV infection CD4 þ and CD8 þ T cells may be less responsive to B7 costimuli due to two different mechanisms: increase in CTLA-4 expression by CD4 þ cells and down-regulation of CD28 by CD8 þ cells.

Cell surface expression of the HIV-1 envelope glycoproteins is directed from intracellular CTLA-4-containing regulated secretory granules

“…Cell surface expression of CTLA-4 increases during HIV protein production (ref. 31 and supporting information), suggesting that CTLA-4-containing granules are apparently signaled to translocate to the plasma membrane at some late stage of HIV virus assembly. Because of their shared residence in granules, CTLA-4 and Env are recruited concomitantly to the cell surface (Fig.…”

CD40 Ligand Trimer and IL-12 Enhance Peripheral Blood Mononuclear Cells and CD4+ T Cell Proliferation and Production of IFN-γ in Response to p24 Antigen in HIV-Infected Individuals: Potential Contribution of Anergy to HIV-Specific Unresponsiveness

“…It is also possible that HIV-specific cells are present, but they are unresponsive. HIV-specific cells could be unresponsive due to specific tolerance to HIV Ags or to a global unresponsiveness as a consequence of HIV infection, e.g., through cytokine dysregulation (23)(24)(25), cell surface molecule modulation (26), or other mechanisms. HIV Ags coming into contact with CD4 ϩ T cells in the absence of the appropriate costimulatory molecules or the proper cytokine milieu could induce unresponsiveness in HIV-specific CD4 ϩ T cells (27)(28)(29).…”

Characterization of the Immune Status of CD8+T Cells in Oral Lesions of Human Immunodeficiency Virus-Infected Persons with Oropharyngeal Candidiasis

“…We also attempted to evaluate CD40L and CTLA-4 on the CD8 ϩ cells in these studies, but results demonstrated little to no expression. This may be a function of the cellular phenotype where CD40L and CTLA-4 are expressed more on CD4 ϩ than on CD8 ϩ T cells (26), which was confirmed by analyzing PHA-activated PBLs. The costimulatory molecule CD28 is also a useful marker for activation, but similar to CD40L and CTLA-4 in tissue, the CD8 ϩ cells had little to no detectable expression of CD28.…”