CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

Abstract

The cellular and molecular mechanisms of dysfunction and depletion of CD4 ؉ T lymphocytes over the course of human immunodeficiency virus type 1 (HIV-1) infection are still incompletely understood, but chronic immune activation is thought to play an important role in disease progression. We studied CD4 ؉ T-cell biology in CD4C/HIV transgenic (Tg) mice, in which Nef expression is sufficient to induce a severe AIDS-like disease including a preferential decrease of CD4 ؉ T cells. We show here that Nef-expressing Tg CD4 ؉ T cells exhibit an activated/memory-like phenotype which appears to be independent of antigenic stimulation, as documented in experiments involving breeding with AD10 TcR Tg mice. In addition, in vivo bromodeoxyuridine incorporation showed that a larger proportion of Tg than non-Tg CD4 ؉ T cells entered the S phase. However, in vitro, Tg CD4 ؉ T cells were found to have a very limited capacity to divide in response to stimulation with anti-CD3 and anti-CD28 or in allogeneic mixed leukocyte reactions. Interestingly, despite these observations, the deletion of Tg CD4 ؉ T cells had little impact on the development of other AIDS-like organ phenotypes. Thus, the Nef-induced chronic activation of CD4 ؉ T cells may exhaust the T-cell pool and may contribute to the thymic atrophy and the low number of CD4 ؉ T cells observed in these Tg mice.

T Cell Activation and Proliferation Characteristic for HIV-Nef Transgenic Mice Is Lymphopenia Induced

“…Studies by Jolicoeur and coworkers (19) in CD4C/HIV-Nef tg mice have shown similar thymic depletion and increased peripheral T cell activation and proliferation as we report here. To test whether this increased activation was TCR dependent, these investigators crossed their Nef tg mice with TCR tg mice (AD10).…”

“…Upon viral challenge with vesicular stomatitis virus and lymphocytic choriomeningitis virus, it appeared that Nef tg T cells were less capable of inducing virusspecific CTL responses and to clear the virus (15). In line with this finding, Nef tg T cells had decreased in vitro proliferative capacities compared with wild-type (wt) T cells (15,18,19).…”

“…To test whether this increased activation was TCR dependent, these investigators crossed their Nef tg mice with TCR tg mice (AD10). Also in these double-tg mice CD4 T cells had an activated E/M phenotype, suggesting an intrinsic Ag-independent effect of Nef on T cell activation (19). However, it was shown that under lymphopenic conditions TCR tg CD4 T cells can proliferate in the absence of their cognate Ag, resulting in the acquisition of an E/M-like phenotype (27), thereby questioning the former interpretation of their results.…”

“…Correlation between the expression levels of activation markers and the amount of Nef protein expressed in CD4 T cells in Nef tg mice further suggests an in vivo role for Nef in T cell activation (19). In these Nef tg mice, different CD4 populations, designated as CD4 high and CD4 low , with respectively low and high Nef expression have been described previously (19).…”

“…In all of these tg mouse strains, depletion of the T cell compartment is observed. In addition, T cells derived from secondary lymphoid organs showed increased activation (15,18,19). Upon viral challenge with vesicular stomatitis virus and lymphocytic choriomeningitis virus, it appeared that Nef tg T cells were less capable of inducing virusspecific CTL responses and to clear the virus (15).…”