Cellular metabolism governs the susceptibility of CD4 T cells to HIV-1 infection. Multiple early post-fusion steps of HIV-1 replication are restricted in resting peripheral blood CD4 T cells; however, molecular mechanisms that underlie metabolic control of these steps remain undefined. Here, we show that mTOR activity following T cell stimulatory signals overcomes metabolic restrictions in these cells by enabling the expansion of dNTPs to fuel HIV-1 reverse transcription (RT), as well as increasing acetyl-CoA to stabilize microtubules that transport RT products. We find that catalytic mTOR inhibition diminishes the expansion of pools of both of these metabolites by limiting glucose and glutamine utilization in several pathways, thereby suppressing HIV-1 infection. We demonstrate how mTOR-coordinated biosyntheses enable the early steps of HIV-1 replication, add metabolic mechanisms by which mTOR inhibitors block HIV-1, and identify some metabolic modules downstream of mTOR as druggable targets for HIV-1 inhibition.
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Memory B cells (MBCs) and plasma cells (PCs) constitute the two cellular outputs of germinal center (GC) responses that together facilitate long-term humoral immunity. Although expression of the transcription factor BLIMP-1 identifies cells undergoing PC differentiation, no such marker exists for cells committed to the MBC lineage. Here, we report that the chemokine receptor CCR6 uniquely marks MBC precursors in both mouse and human GCs. CCR6+ GC B cells were highly enriched within the GC light zone (LZ), were the most quiescent of all GC B cells, exhibited a cell-surface phenotype and gene expression signature indicative of an MBC transition, and possessed the augmented response characteristics of MBCs. MBC precursors within the GC LZ predominantly possessed a low affinity for antigen but also included cells from within the high-affinity pool. These data indicate a fundamental dichotomy between the processes that drive MBC and PC differentiation during GC responses.
Copyright © 2017 Elsevier Inc. All rights reserved.

Herpes zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. Whereas a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax. Vaccination induces robust antigen-specific antibody, plasmablasts, and CD4+ T cells yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets, such as transcriptomic and metabolomics signatures, cell populations, and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids, and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.
Copyright © 2017 Elsevier Inc. All rights reserved.

Decreased NK cell numbers and impairment of NK cell function are reported in patients with multiple sclerosis (MS). Interleukin-7 (IL-7) is a member of the common gamma-chain (γc) cytokine superfamily that has well documented roles in lymphocyte development and homeostasis. The interleukin-7 receptor α chain (IL-7Rα) gene was identified as a top non-major histocompatibility complex-linked risk locus for MS. The objective of this study was to test biological function of IL-7/IL-7Rα on NK cells in MS patients. We observed markedly lower IL-7 levels in MS sera, and relatively higher IL-7Rα expression in NK cells of MS. Upon IL-7 stimulation, IL-7Rα on NK cells from MS patients was significantly down-regulated compared with healthy controls (HCs). IL-7 induced a higher increase of IFN-γ production in CD56(bright) NK cells and a pronounced enhancement of cytotoxicity in NK cells from MS. IL-7 did not impact the proliferation of NK cells differently in MS and HC. In contrast, IL-7 promoted a higher survival of CD56(bright) NK cells in MS and inhibited their apoptosis by increasing Bcl-2 expression, but had no effect on CD56(dim) NK cell survival in MS. In conclusion, MS patients have lower serum IL-7 and a higher membrane IL-7Rα expression on CD56(bright) NK cells. The skew at the IL-7 and IL-7Rα level influences functional responsiveness of NK cells in MS.
Copyright © 2014 Elsevier B.V. All rights reserved.

The presence of autoantibodies in New Zealand Black (NZB) mice suggests a B cell tolerance defect however the nature of this defect is unknown. To determine whether defects in B cell anergy contribute to the autoimmune phenotype in NZB mice, soluble hen egg lysozyme (sHEL) and anti-HEL Ig transgenes were bred onto the NZB background to generate double transgenic (dTg) mice. NZB dTg mice had elevated levels of anti-HEL antibodies, despite apparently normal B cell functional anergy in-vitro. NZB dTg B cells also demonstrated increased survival and abnormal entry into the follicular compartment following transfer into sHEL mice. Since this process is dependent on BAFF, BAFF serum and mRNA levels were assessed and were found to be significantly elevated in NZB dTg mice. Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process. Although NZB mice had modestly elevated BAFF, the enhanced NZB B cell survival response appeared to result from an altered response to BAFF. In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production. The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help.