Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection

Abstract

Loss of intracellular TRAF1 expression correlates with CD8+ T cell exhaustion and contributes to increased viral load at the chronic stage of HIV and LCMV infection, a phenotype that can be reversed by IL-7 stimulation together with 4-1BB agonist.

Anti-GITR Agonist Therapy Intrinsically Enhances CD8 T Cell Responses to Chronic Lymphocytic Choriomeningitis Virus (LCMV), Thereby Circumventing LCMV-Induced Downregulation of Costimulatory GITR Ligand on APC

“…Agonist anti-OX40 has no effect on viral load in LCMV cl 13 infection (11), and agonist anti-4-1BB had minimal therapeutic effect when administered during the chronic stage of LCMV cl 13 infection due to the loss of a key signaling adaptor, TNFR-associated factor (TRAF)1, downstream of 4-1BB, with similar findings in T cells from chronically HIV-infected donors (12). Although anti-4-1BB demonstrated efficacy when combined with IL-7, which restores TRAF1 levels (12), there is growing concern that agonist therapies targeting T cell cosignaling molecules such as 4-1BB and CD28 or soluble factors such as IL-21 may induce indiscriminate or overzealous expansion of CD8 T cells and result in immune pathology (13)(14)(15)(16)(17)(18). Therefore, it remains a significant challenge to identify a T cell costimulatory molecule that is both safe and effective in improving immune function and control of viral infections.…”

“…In addition to self-limiting inflammation, there are also examples of ineffective therapies targeting T cell costimulatory molecules. During chronic LCMV infection in mouse or HIV infection in humans, TRAF1 is lost in virus-specific CD8 T cells so 4-1BB cannot signal, and therefore anti-4-1BB is ineffective as a therapy (12). Even when 4-1BB signaling was restored by IL-7 treatment to upregulate TRAF1, these effects were not ideal in that they resulted in an increase in the total number, but not the proportion of LCMV-specific T cells (12).…”

“…During chronic LCMV infection in mouse or HIV infection in humans, TRAF1 is lost in virus-specific CD8 T cells so 4-1BB cannot signal, and therefore anti-4-1BB is ineffective as a therapy (12). Even when 4-1BB signaling was restored by IL-7 treatment to upregulate TRAF1, these effects were not ideal in that they resulted in an increase in the total number, but not the proportion of LCMV-specific T cells (12). This may be because anti-4-1BB agonist treatment can expand bystander 4-1BB + memory T cells (16)(17)(18).…”

“…there are multiple costimulatory receptors and ligands present, and the addition of exogenous GITR costimulation is redundant and therefore does not further enhance the response. However, at later time points when coinhibitory molecules predominate and costimulatory 4-1BB is desensitized (12,44), exogenous GITR costimulation is efficacious.…”

The BCL-2 pro-survival protein A1 is dispensable for T cell homeostasis on viral infection

“…42 In short, brain, liver, lung, spleen and kidney were collected in MEM 2% FCS and frozen at − 80°C before further analysed. Organs were homogenised and supernatant dilutions were used to infect monolayers of MC57 cells (8 × 10 5 per ml), Cells were overlayed with 2% methyl cellulose (Fluka #64620) in DME and plates were incubated at 37°C, 5% CO 2 for 48 h. Viral plaque staining was performed after fixation of the cells with 4% Formalin-PBS and permeabilization with 0.1% Triton X (FLUKA #93418) with VL-4 rat anti-LCMV monoclonal antibody (WEHI Antibody Facility, Melbourne, VIC, Australia) followed by Peroxidase-conjugated AffiniPure goat anti-rat IgG (H+L) antibodies (Jackson ImmunoResearch Laboratories, West Grove, PA, USA #112-035-003).…”