Generalized immune activation as a direct result of activated CD4+ T cell killing

Background: In addition to progressive CD4+ T cell immune deficiency, HIV infection is characterized by generalized immune activation, thought to arise from increased microbial exposure resulting from diminishing immunity. Results: Here we report that, in a virus-free mouse model, conditional ablation of activated CD4+ T cells, the targets of immunodeficiency viruses, accelerates their turnover and produces CD4+ T cell immune deficiency. More importantly, activated CD4+ T cell killing also results in generalized immune activation, which is attributable to regulatory CD4+ T cell insufficiency and preventable by regulatory CD4+ T cell reconstitution. Immune activation in this model develops independently of microbial exposure. Furthermore, microbial translocation in mice with conditional disruption of intestinal epithelial integrity affects myeloid but not T cell homeostasis. Conclusions: Although neither ablation of activated CD4+ T cells nor disruption of intestinal epithelial integrity in mice fully reproduces every aspect of HIV-associated immune dysfunction in humans, ablation of activated CD4+ T cells, but not disruption of intestinal epithelial integrity, approximates the two key immune alterations in HIV infection: CD4+ T cell immune deficiency and generalized immune activation. We therefore propose activated CD4+ T cell killing as a common etiology for both immune deficiency and activation in HIV infection

Negative Selection by an Endogenous Retrovirus Promotes a Higher-Avidity CD4+ T Cell Response to Retroviral Infection

Effective T cell responses can decisively influence the outcome of retroviral infection. However, what constitutes protective T cell responses or determines the ability of the host to mount such responses is incompletely understood. Here we studied the requirements for development and induction of CD4+ T cells that were essential for immunity to Friend virus (FV) infection of mice, according to their TCR avidity for an FV-derived epitope. We showed that a self peptide, encoded by an endogenous retrovirus, negatively selected a significant fraction of polyclonal FV-specific CD4+ T cells and diminished the response to FV infection. Surprisingly, however, CD4+ T cell-mediated antiviral activity was fully preserved. Detailed repertoire analysis revealed that clones with low avidity for FV-derived peptides were more cross-reactive with self peptides and were consequently preferentially deleted. Negative selection of low-avidity FV-reactive CD4+ T cells was responsible for the dominance of high-avidity clones in the response to FV infection, suggesting that protection against the primary infecting virus was mediated exclusively by high-avidity CD4+ T cells. Thus, although negative selection reduced the size and cross-reactivity of the available FV-reactive naïve CD4+ T cell repertoire, it increased the overall avidity of the repertoire that responded to infection. These findings demonstrate that self proteins expressed by replication-defective endogenous retroviruses can heavily influence the formation of the TCR repertoire reactive with exogenous retroviruses and determine the avidity of the response to retroviral infection. Given the overabundance of endogenous retroviruses in the human genome, these findings also suggest that endogenous retroviral proteins, presented by products of highly polymorphic HLA alleles, may shape the human TCR repertoire that reacts with exogenous retroviruses or other infecting pathogens, leading to interindividual heterogeneity

Resurrection of endogenous retroviruses in antibody-deficient mice

International audienceThe mammalian host has developed a long-standing symbiotic relationship with a considerable number of microbial species. These include the microbiota on environmental surfaces, such as the respiratory and gastrointestinal tracts, and also endogenous retroviruses (ERVs), comprising a substantial fraction of the mammalian genome. The long-term consequences for the host of interactions with these microbial species can range from mutualism to parasitism and are not always completely understood. The potential effect of one microbial symbiont on another is even less clear. Here we study the control of ERVs in the commonly used C57BL/6 (B6) mouse strain, which lacks endogenous murine leukaemia viruses (MLVs) able to replicate in murine cells. We demonstrate the spontaneous emergence of fully infectious ecotropic MLV in B6 mice with a range of distinct immune deficiencies affecting antibody production. These recombinant retroviruses establish infection of immunodeficient mouse colonies, and ultimately result in retrovirus-induced lymphomas. Notably, ERV activation in immunodeficient mice is prevented in husbandry conditions associated with reduced or absent intestinal microbiota. Our results shed light onto a previously unappreciated role for immunity in the control of ERVs and provide a potential mechanistic link between immune activation by microbial triggers and a range of pathologies associated with ERVs, including cancer

Generalized immune activation as a direct result of activated CD4⁺T cell killing

Abstract Background In addition to progressive CD4+ T cell immune deficiency, HIV infection is characterized by generalized immune activation, thought to arise from increased microbial exposure resulting from diminishing immunity. Results Here we report that, in a virus-free mouse model, conditional ablation of activated CD4+ T cells, the targets of immunodeficiency viruses, accelerates their turnover and produces CD4+ T cell immune deficiency. More importantly, activated CD4+ T cell killing also results in generalized immune activation, which is attributable to regulatory CD4+ T cell insufficiency and preventable by regulatory CD4+ T cell reconstitution. Immune activation in this model develops independently of microbial exposure. Furthermore, microbial translocation in mice with conditional disruption of intestinal epithelial integrity affects myeloid but not T cell homeostasis. Conclusions Although neither ablation of activated CD4+ T cells nor disruption of intestinal epithelial integrity in mice fully reproduces every aspect of HIV-associated immune dysfunction in humans, ablation of activated CD4+ T cells, but not disruption of intestinal epithelial integrity, approximates the two key immune alterations in HIV infection: CD4+ T cell immune deficiency and generalized immune activation. We therefore propose activated CD4+ T cell killing as a common etiology for both immune deficiency and activation in HIV infection. See minireview http://www.jbiol.com/content/8/10/91</p

Race between Retroviral Spread and CD4+ T-Cell Response Determines the Outcome of Acute Friend Virus Infection▿

Retroviruses can establish persistent infection despite induction of a multipartite antiviral immune response. Whether collective failure of all parts of the immune response or selective deficiency in one crucial part underlies the inability of the host to clear retroviral infections is currently uncertain. We examine here the contribution of virus-specific CD4+ T cells in resistance against Friend virus (FV) infection in the murine host. We show that the magnitude and duration of the FV-specific CD4+ T-cell response is directly proportional to resistance against acute FV infection and subsequent disease. Notably, significant protection against FV-induced disease is afforded by FV-specific CD4+ T cells in the absence of a virus-specific CD8+ T-cell or B-cell response. Enhanced spread of FV infection in hosts with increased genetic susceptibility or coinfection with Lactate dehydrogenase-elevating virus (LDV) causes a proportional increase in the number of FV-specific CD4+ T cells required to control FV-induced disease. Furthermore, ultimate failure of FV/LDV coinfected hosts to control FV-induced disease is accompanied by accelerated contraction of the FV-specific CD4+ T-cell response. Conversely, an increased frequency or continuous supply of FV-specific CD4+ T cells is both necessary and sufficient to effectively contain acute infection and prevent disease, even in the presence of coinfection. Thus, these results suggest that FV-specific CD4+ T cells provide significant direct protection against acute FV infection, the extent of which critically depends on the ratio of FV-infected cells to FV-specific CD4+ T cells

<i>Emv2</i>-selected CD4⁺ T cells mount a predominantly high-avidity response.

<p>(A–C) CD45.2⁺ (<i>Ptprc</i>^2/2) CD4⁺ T cells isolated from either B6 (B6-EF4.1) or <i>Emv2</i>-deficient B6 (B6-EF4.1 <i>Emv2</i>^−/−) EF4.1 donor mice were adoptively transferred into <i>Ptprc</i>^1/2 B6 recipients that were infected with FV the same day and analyzed 7 days later. (A) Absolute number of total, Vα2 or non-Vα2 FV-responding (CD44^hi) donor (CD45.2⁺CD45.1⁻) CD4⁺ T cells isolated from the spleens of recipient mice according to donor type. (B) Flow cytometric example and (C) frequency of high-avidity Vα2 cells in responding CD4⁺ T cells according to donor type. In (A) and (C) each symbol is an individual mouse.</p

Depth of Vα2 or non-Vα2 env-specific CD4⁺ T cell repertoires.

<p>(A–C) Vα2 or non-Vα env_124-138L-reactive hybridoma T cell lines were derived from <i>Emv2</i>^+/+ (B6-EF4.1) or <i>Emv2</i>^−/− (B6-EF4.1 <i>Emv2</i>^−/−) EF4.1 mice and tested for reactivity against a library of env_126-138 peptide epitopes. The amino acid residues in positions 128 (A), 129 (B) and 133 (C) that elicited at least 40% of the maximal response are listed in the order of preference by the individual clones.</p

<i>Emv2</i> preferentially selects against non-Vα2 env-specific CD4⁺ T cells.

<p>(A) Dose-response to env_124-138L stimulation of CD4⁺ T cells isolated from either B6 (B6-EF4.1) or <i>Emv2</i>-deficient B6 (B6-EF4.1 <i>Emv2</i>^−/−) EF4.1 mice. (B) Frequency of env_124-138L-specific cells in Vα2 or non-Vα2 primary CD4⁺ T cells from the same donors. (C) Functional avidity of <i>Emv2</i>-selected (B6-EF4.1) or -nonselected (B6-EF4.1 <i>Emv2</i>^−/−) EF4.1 CD4⁺ T cells for env_124-138L. (D) Frequency of Vα2 cells in env_124-138L-specific CD4⁺ T cells from the same donors as a function of peptide concentration. (E) Frequency of env_124-138Y-specific cells in Vα2 or non-Vα2 primary CD4⁺ T cells from the same donors. (F) Functional avidity of <i>Emv2</i>-selected (B6-EF4.1) or -nonselected (B6-EF4.1 <i>Emv2</i>^−/−) EF4.1 CD4⁺ T cells for env_124-138Y. Numbers in (C) and (F) represent the ED₅₀. Data in (A–F) are the means ± SEM (<i>n</i> = 9–12) of 18-hr stimulations from 3 experiments.</p