Reservoirs of HIV maintained in anatomic compartments during antiretroviral therapy prevent HIV eradication. However, mechanisms driving their persistence and interventions to control them remain elusive. Here we report the presence of an inducible HIV reservoir within antigen-specific CD4+T cells in the central nervous system of a 59-year-old male with progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome (PML-IRIS). HIV production during PML-IRIS was suppressed by modulating inflammation with corticosteroids; selection of HIV drug resistance caused subsequent breakthrough viremia. Therefore, inflammation can influence the composition, distribution and induction of HIV reservoirs, warranting it as a key consideration for developing effective HIV remission strategies.
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Adoptive cellular therapy using chimeric antigen receptors (CARs) has revolutionized our treatment of relapsed B cell malignancies and is currently being integrated into standard therapy. The impact of selecting specific T cell subsets for CAR transduction remains under investigation. Previous studies demonstrated that effector T cells derived from naive, rather than central memory T cells mediate more potent antitumor effects. Here, we investigate a method to skew CAR transduction toward naive T cells without physical cell sorting. Viral-mediated CAR transduction requires ex vivo T cell activation, traditionally achieved using antibody-mediated strategies. CD81 is a T cell costimulatory molecule that when combined with CD3 and CD28 enhances naive T cell activation. We interrogate the effect of CD81 costimulation on resultant CAR transduction. We identify that upon CD81-mediated activation, naive T cells lose their identifying surface phenotype and switch to a memory phenotype. By prelabeling naive T cells and tracking them through T cell activation and CAR transduction, we document that CD81 costimulation enhanced naive T cell activation and resultantly generated a CAR T cell product enriched with naive-derived CAR T cells.
Copyright © 2022 the Author(s). Published by PNAS.

Recent studies highlight the potentially important role of neoepitopes in breaking immune tolerance in type 1 diabetes. T cell reactivity to these neoepitopes has been reported, but how this response compares quantitatively and phenotypically with previous reports on native epitopes is not known. Thus, an understanding of the relationship between native and neoepitopes and their role as tolerance breakers or disease drivers in type 1 diabetes is required. We set out to compare T cell reactivity and phenotype against a panel of neo- and native islet autoantigenic epitopes to examine how this relates to stages of type 1 diabetes development.
Fifty-four subjects comprising patients with T1D, and autoantibody-positive unaffected family members were tested against a panel of neo- and native epitopes by ELISPOT (IFN-γ, IL-10, and IL-17). A further subset of two patients was analyzed by Single Cell Immune Profiling (RNAseq and TCR α/β) after stimulation with pools of native and neoepitope peptides.
T cell responses to native and neoepitopes were present in patients with type 1 diabetes and at-risk subjects, and overall, there were no significant differences in the frequency, magnitude, or phenotype between the two sets of peptide stimuli. Single cell RNAseq on responder T cells revealed a similar profile in T1D patients stimulated with either neo- or native epitopes. A pro-inflammatory gene expression profile (TNF-α, IFN-γ) was dominant in both native and neoepitope stimulated T cells. TCRs with identical clonotypes were found in T cell responding to both native and neoepitopes.
These data suggest that in peripheral blood, T cell responses to both native and neoepitopes are similar in terms of frequency and phenotype in patients with type 1 diabetes and high-risk unaffected family members. Furthermore, using a combination of transcriptomic and clonotypic analyses, albeit using a limited panel of peptides, we show that neoepitopes are comparable to native epitopes currently in use for immune-monitoring studies.
Copyright © 2021 Arif, Pujol-Autonell, Kamra, Williams, Yusuf, Domingo-Vila, Shahrabi, Pollock, Khatri, Peakman, Tree and Lorenc.

The human fetal immune system begins to develop early during gestation; however, factors responsible for fetal immune-priming remain elusive. We explored potential exposure to microbial agents in utero and their contribution toward activation of memory T cells in fetal tissues. We profiled microbes across fetal organs using 16S rRNA gene sequencing and detected low but consistent microbial signal in fetal gut, skin, placenta, and lungs in the 2nd trimester of gestation. We identified several live bacterial strains including Staphylococcus and Lactobacillus in fetal tissues, which induced in vitro activation of memory T cells in fetal mesenteric lymph node, supporting the role of microbial exposure in fetal immune-priming. Finally, using SEM and RNA-ISH, we visualized discrete localization of bacteria-like structures and eubacterial-RNA within 14th weeks fetal gut lumen. These findings indicate selective presence of live microbes in fetal organs during the 2nd trimester of gestation and have broader implications toward the establishment of immune competency and priming before birth.
Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.

It remains unknown how different training intensities and volumes chronically impact circulating lymphocytes and cellular adhesion molecules. First, we aimed to monitor changes in NK and T cells over a training season and relate these to training load. Second, we analyzed effects of training differences between swimmers on these cells. Finally, we examined if changes in lymphocytes were associated with sICAM-1 concentrations.
We analyzed weekly training volume, training intensity, proportions of T and NK cells and serum sICAM-1 in eight sprint (SS) and seven middle-distance swimmers (MID) at three points over a 16-week training period: at the start (t0), after 7 weeks of increased training load (t7) and after 16 weeks, including 5-day taper (t16).
Training volume of all swimmers was statistically higher and training intensity lower from t0-t7 compared to t7-t16 (p = 0.001). Secondly, training intensity was statistically higher in SS from t0-t7 (p = 0.004) and t7-t16 (p = 0.015), while MID had a statistically higher training volume from t7-t16 (p = 0.04). From t0-t7, NK (p = 0.06) and CD45RA+CD45RO+CD4+ cells (p < 0.001) statistically decreased, while CD45RA-CD45RO+CD4+ cells (p = 0.024) statistically increased. In a subgroup analysis, SS showed statistically larger increases in NK cells from t7-t16 than MID (p = 0.012). Lastly, sICAM-1 concentrations were associated with changes in CD45RA-CDRO+CD4+ cells (r = - 0.656, p = 0.08).
These results indicate that intensified training in swimmers resulted in transient changes in T and NK cells. Further, NK cells are sensitive to high training volumes. Lastly, sICAM-1 concentrations may be associated with the migration and maturation of CD4+ cells in athletes.