ART duration and immunometabolic state determine efficacy of DC-based treatment restoring functional HIV- specific CD8+ T cells in Chronic PLWH.

Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated in detail. Here, we studied the association of ART duration with memory subsets, exhaustion and metabolic profiles of CD8+ T cells from PLWH and improvement of polyfunctional and effector HIV-1 specific responses after stimulation with Gag-adjuvant-primed DC. HIV-1-specific CD8+ T cell responses from a larger proportion PLWH on ART for more than 10 years (LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro. In contrast, CD8+ T cells from PLWH on ART for less than a decade (ST-ARTp) were less responsive to DC treatment and functional improvement was limited in this group. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolytic induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+PD1- cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells. Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines.

Naive arthritogenic SKG T cells have a defect in anergy and a repertoire pruned by superantigen

How autoreactive CD4 T cells develop to cause rheumatoid arthritis remains unknown. We used a reporter for antigen-receptor signaling in the SKG autoimmune arthritis model to profile a T cell subpopulation enriched for arthritogenic naive CD4 T cells before arthritis onset by bulk and single cell RNA and T cell antigen-receptor (TCR) sequencing. Our analyses reveal that despite their impaired proximal TCR signaling, a subset of SKG naive CD4 T cells that have recently encountered endogenous antigen upregulate gene programs associated with positive regulation of T cell activation and cytokine signaling at higher levels than wild type cells in the pre-disease state. These arthritogenic cells also induce genes associated with negative regulation of T cell activation but do so less efficiently than wild type cells. Furthermore, their TCR sequences exhibit a previously unrecognized biased peripheral TCR Vβ repertoire likely driven by endogenous viral superantigens. These particular Vβs, known to recognize endogenous mouse mammary tumor virus (MMTV) superantigen, are further expanded in arthritic joints. Our results demonstrate that autoreactive naive CD4 T cells which recognize endogenous viral superantigens are poised to cause disease by their altered transcriptome.

Ovariectomy increases paclitaxel-induced mechanical hypersensitivity and reduces anti-inflammatory CD4+ T cells in the dorsal root ganglion of female mice

Chemotherapy is often dose limiting due to the emergence of a debilitating neuropathy. IL-10 and IL-4 are protective against peripheral neuropathy, yet the cell source is unknown. Using flow cytometry, we found that naïve females had a greater frequency of anti-inflammatory CD4+ T cells in the dorsal root ganglion (DRG) than males. In response to paclitaxel, females had reduced hypersensitivity and a greater frequency of anti-inflammatory CD4+ T cells (FoxP3, IL-10, IL-4) in the DRG than ovariectomized and male mice. These findings support a model in which estrogen promotes anti- inflammatory CD4+ T cells in female DRG to suppress peripheral neuropathy.

Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts

A key unknown of the functional space in tumor immunity is whether CD4 T cells depend on intratumoral MHCII cancer antigen recognition. MHCII-expressing, antigen-presenting cancer-associated fibroblasts (apCAFs) have been found in breast and pancreatic tumors and are considered to be immunosuppressive. This analysis shows that antigen-presenting fibroblasts are frequent in human lung non-small cell carcinomas, where they seem to actively promote rather than suppress MHCII immunity. Lung apCAFs directly activated the TCRs of effector CD4 T cells and at the same time produced C1q, which acted on T cell C1qbp to rescue them from apoptosis. Fibroblast-specific MHCII or C1q deletion impaired CD4 T cell immunity and accelerated tumor growth, while inducing C1qbp in adoptively transferred CD4 T cells expanded their numbers and reduced tumors. Collectively, we have characterized in the lungs a subset of antigen-presenting fibroblasts with tumor-suppressive properties and propose that cancer immunotherapies might be strongly dependent on in situ MHCII antigen presentation.

Effect of Exercise on Acute Senescent Lymphocyte Counts: A Systematic Review and Meta-Analysis

<b><i>Background:</i></b> Highly differentiated, senescent lymphocytes are pro-inflammatory and contribute to age-related systemic inflammation, called inflammageing. There are several reports of acute changes in senescent lymphocyte counts post exercise, which potentially have consequences for systemic inflammation. However, there is little consensus since the studies differ with respect to participants, exercise protocols, cellular markers assessed, and the time point of assessment post exercise. <b><i>Objective:</i></b> We performed a systematic review and meta-analysis to assess the impact of exercise on senescent lymphocyte counts in blood immediately, 1 h and 2 h post exercise. <b><i>Methods:</i></b> The search was performed in PubMed (MEDLINE), Web of Science, Embase, Scopus, and Cochrane, on January 11, 2021. The 13 studies selected tested aerobic exercise effects, mainly in young men. They assessed the counts of lymphocytes (CD4 T cells, CD8 T cells, and NK cells), with the following immune cell marker combinations: KLRG1+, CD57+ (only NK cells), EMRA T cells (CD45RA+CCR7−CD28−CD27−), CD28−CD27−, KLRG1+CD28−, and CD28−. Independent extraction of articles was done by 2 researchers. <b><i>Results:</i></b> Standardized mean difference (SMD) and 95% confidence interval between baseline and post exercise showed significant increase (SMD &#x3e;0.9, <i>p</i> &#x3c; 0.003) in all types of senescent lymphocytes counts immediately post exercise. At 1 h post exercise, senescent CD4 T cells returned to baseline values (<i>p</i> = 0.74), CD8 T cells were reduced (−0.26 [−0.41; −0.11], <i>p</i> = 0.001), and senescent NK cells were raised (0.62 [0.14; 1.10], <i>p</i> = 0.01) above baseline. By 2 h post exercise, senescent CD4 T cells were reduced (−0.94 [−1.40; −0.48], <i>p</i> &#x3c; 0.001), CD8 T cells remained below baseline (−0.53 [−1.04; −0.009], <i>p</i> = 0.04), and NK cells had returned to baseline values (−0.29 [−0.64; 0.07], <i>p</i> = 0.11). The main determinants of heterogeneity between studies were cytomegalovirus (CMV) serostatus and the characteristics of exercise protocols. CMV+ individuals had a higher immediate lymphocytosis and 1 h post lymphopenia than CMV− individuals. Exercise performed at higher intensities and shorter durations led to higher magnitude of change in senescent lymphocyte counts at all time-points. <b><i>Conclusion:</i></b> The differing effects of exercise on senescent NK cells and CD4 and CD8 T cells suggest differing susceptibility to factors modulating lymphocyte extravasation such as adrenaline and exercise intensity.

Erythroid Differentiation Regulator 1 Strengthens TCR Signaling by Enhancing PLCγ1 Signal Transduction Pathway

Erythroid differentiation regulator 1 (Erdr1) has previously been reported to control thymocyte selection via TCR signal regulation, but the effect of Erdr1 as a TCR signaling modulator was not studied in peripheral T cells. In this report, it was determined whether Erdr1 affected TCR signaling strength in CD4 T cells. Results revealed that Erdr1 significantly enhanced the anti-TCR antibody-mediated activation and proliferation of T cells while failing to activate T cells in the absence of TCR stimulation. In addition, Erdr1 amplified Ca2+ influx and the phosphorylation of PLCγ1 in CD4 T cells with the TCR stimuli. Furthermore, NFAT1 translocation into nuclei in CD4 T cells was also significantly promoted by Erdr1 in the presence of TCR stimulation. Taken together, our results indicate that Erdr1 positively modulates TCR signaling strength via enhancing the PLCγ1/Ca2+/NFAT1 signal transduction pathway.