The AIDS-Like Disease of CD4C/Human Immunodeficiency Virus Transgenic Mice Is Associated with Accumulation of Immature CD11b^HiDendritic Cells

Abstract

CD4C/human immunodeficiency virus (HIV) transgenic mice develop an AIDS-like disease. We used this model to study the effects of HIV-1 on dendritic cells (DC). We found a progressive decrease in total DC numbers in the lymph nodes, with a significant accumulation of CD11bHi DC. In the thymus, the recovery of transgenic CD8␣؉ DC had a tendency to be lower. Spleen DC were augmented in the marginal zone. Transgenic DC showed a decreased capacity to present antigen in vitro, consistent with their reduced major histocompatibility complex class II expression and impaired maturation profile. The accumulation of immature DC may contribute to disease and may reflect an adaptive advantage for the virus by favoring its replication and preventing the generation of fully functional antiviral responses.Dendritic cells (DC) are involved in the generation of immune responses as well as in the selection and maintenance of the T-cell repertoire (3,46,54,75,78,81). During human immunodeficiency virus type 1 (HIV-1) infection, Langherans cells and DC at the mucosal surfaces are the earliest cell types to be exposed to HIV-1 in vivo and are thought to facilitate transmission of the virus to CD4 ϩ T cells following their migration to the lymph nodes (6, 64; reviewed in references 43, 71, and 86). HIV-1 is known to replicate preferentially in immature DC (32), and HIV-1 footprints have been detected in blood-, adenoid/tonsil-, and skin-derived DC from HIVpositive individuals (12,28,45,49,68), but not in all studies (5,40). This controversy about the extent of infection of human DC in vivo is also apparent regarding the effects of HIV-1 on DC differentiation, phenotype, and function, where a consensus has been difficult to reach, given the various sources of DC being studied, their stages of differentiation, their mode of isolation and culture, and the various stimuli used (7,43,86). It is therefore not clear whether and how HIV-1 affects DC populations and their function. Neither is it known whether "myeloid" and "plasmacytoid" DC subpopulations, the latter being most probably of lymphoid origin (79), are affected differently by HIV-1.To gain insight into the pathogenesis of HIV-1, we previously generated CD4C/HIV transgenic mice, which express HIV-1 gene products in CD4ϩ T cells and in cells of the macrophage/dendritic lineages and develop a severe AIDS-like disease. This disease is characterized by atrophy of the lymphoid organs and by gradual and preferential loss of CD4 ϩ T cells and of their functions (34, 35). These mice also exhibit an impaired capacity to generate germinal center reactions and harbor hyperresponsive B cells and serum autoantibody (65).Here we report our study on DC in these transgenic mice. MATERIALS AND METHODS Mice. The CD4C/HIVMutA transgenic mice have been described previously (35). Sex-matched littermates were used between 6 and 20 weeks of age. In order to generate in vitro mixed leukocyte reaction, CD4 ϩ lymphocytes from sexmatched BALB/c mice were used between 6 and 12 weeks of age. For in vitro antige...

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

“…Immature dendritic cells are thought to play an important role in inducing these regulatory suppressor CD4 ϩ T-cell subsets (57). Moreover, dendritic cells from these CD4C/HIV-1 Tg mice were found to have an immature phenotype and to be functionally impaired as disease progresses (48). …”

Altered CD4+ T Cell Phenotype and Function Determine the Susceptibility to Mucosal Candidiasis in Transgenic Mice Expressing HIV-1

“…The availability of CD4C/HIV transgenic (Tg) mice expressing gene products of HIV-1 in immune cells and developing an AIDS-like disease has provided an opportunity to devise a novel model of mucosal candidiasis (12). These CD4C/HIV Tg mice are immunodeficient and exhibit atrophy of lymphoid organs, a preferential depletion of CD4 ϩ T cells, with altered CD4 ϩ T cell proliferation in vitro, loss of CD4 ϩ T cell help, CD4 ϩ T cell and B cell activation and impaired dendritic cell (DC) function (13)(14)(15)(16)(17). In addition, disease of the lung (lymphocytic interstitial pneumonitis), heart (myocytolysis, myocarditis), and kidney (tubulointerstitial nephritis, segmental glomerulosclerosis, microcystic dilatation) develop in these Tg mice (13,18).…”

“…Flow cytometry analysis was performed by gating on CD69 ϩ cells, to determine the percentage of CD4 ϩ T cells expressing each of the cytokines. Bone marrow-derived DCs (BMDCs) were generated using a modification of methods previously described (16,19). BM cells were filtered through a 70-m nylon mesh, washed with HBSS, and cultured with GM-CSF (1000 U/ml; Cedarlane Laboratories) and IL-4 (500 U/ml; Cedarlane Laboratories) in supplemented RPMI 1640.…”

HIV Nef Expression Favors the Relative Preservation of CD4+ T Regulatory Cells That Retain Some Important Suppressive Functions

“…Analysis of spleen of (CD4C/ Nef 3 Foxp3/GFP) double Tg mice confirmed the increased percentage of CD4 (30). This latter cell subset is known to favor accumulation of Treg (31).…”

“…This strongly suggests that Nef is operating independently of these two immune defects known to favor Treg expansion in models of lymphopenia (45,46) or thymic depletion (32) in mice. In addition, results from mixed (Tg:non-Tg) chimeras showed that the relative Treg expansion was observed only in Tg donor cells, but not in non-Tg donor bystander cells, strongly suggesting that Treg dysregulation is unlikely to originate from immature DC known to accumulate in these CD4C/HIV Nef Tg mice (30). The same argument can be used to rule out any circulating factor, such as extracellular Nef (47) or BAFF, which could favor Treg development (48).…”