Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI

Abstract Graft-versus-host disease (GVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (AHSCT). Definitive diagnosis of GVHD is invasive, and biopsies of involved tissues pose a high risk of bleeding and infection. T cells are central to GVHD pathogenesis, and our previous studies in a chronic GVHD mouse model showed that alloreactive CD4+ T cells traffic to the target organs ahead of overt symptoms. Because increased glycolysis is an early feature of T-cell activation, we hypothesized that in vivo metabolic imaging of glycolysis would allow noninvasive detection of liver GVHD as activated CD4+ T cells traffic into the organ. Indeed, hyperpolarized 13C-pyruvate magnetic resonance imaging detected high rates of conversion of pyruvate to lactate in the liver ahead of animals becoming symptomatic, but not during subsequent overt chronic GVHD. Concomitantly, CD4+ T effector memory cells, the predominant pathogenic CD4+ T-cell subset, were confirmed to be highly glycolytic by transcriptomic, protein, metabolite, and ex vivo metabolic activity analyses. Preliminary data from single-cell sequencing of circulating T cells in patients undergoing AHSCT also suggested that increased glycolysis may be a feature of incipient acute GVHD. Metabolic imaging is being increasingly used in the clinic and may be useful in the post-AHSCT setting for noninvasive early detection of GVHD.

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Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2103730118 ◽

2021 ◽

Vol 118 (23) ◽

pp. e2103730118

Author(s):

Yuka Nakajima ◽

Kenji Chamoto ◽

Takuma Oura ◽

Tasuku Honjo

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Critical Role ◽

Cell Subset ◽

Effector Memory ◽

T Cell Subset ◽

Aged Mice ◽

Age Related

CD8+ T cells play a central role in antitumor immune responses that kill cancer cells directly. In aged individuals, CD8+ T cell immunity is strongly suppressed, which is associated with cancer and other age-related diseases. The mechanism underlying this age-related decrease in immune function remains largely unknown. This study investigated the role of T cell function in age-related unresponsiveness to PD-1 blockade cancer therapy. We found inefficient generation of CD44lowCD62Llow CD8+ T cell subset (P4) in draining lymph nodes of tumor-bearing aged mice. In vitro stimulation of naive CD8+ T cells first generated P4 cells, followed by effector/memory T cells. The P4 cells contained a unique set of genes related to enzymes involved in one-carbon (1C) metabolism, which is critical to antigen-specific T cell activation and mitochondrial function. Consistent with this finding, 1C-metabolism–related gene expression and mitochondrial respiration were down-regulated in aged CD8+ T cells compared with young CD8+ T cells. In aged OVA-specific T cell receptor (TCR) transgenic mice, ZAP-70 was not activated, even after inoculation with OVA-expressing tumor cells. The attenuation of TCR signaling appeared to be due to elevated expression of CD45RB phosphatase in aged CD8+ T cells. Surprisingly, strong stimulation by nonself cell injection into aged PD-1–deficient mice restored normal levels of CD45RB and ameliorated the emergence of P4 cells and 1C metabolic enzyme expression in CD8+ T cells, and antitumor activity. These findings indicate that impaired induction of the P4 subset may be responsible for the age-related resistance to PD-1 blockade, which can be rescued by strong TCR stimulation.

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CD8+CD44hi but not CD4+CD44hi memory T cells mediate potent graft antilymphoma activity without GVHD

Blood ◽

10.1182/blood-2010-10-312751 ◽

2011 ◽

Vol 117 (11) ◽

pp. 3230-3239 ◽

Cited By ~ 29

Author(s):

Suparna Dutt ◽

Jeanette Baker ◽

Holbrook E. Kohrt ◽

Neeraja Kambham ◽

Mrinmoy Sanyal ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Memory T Cells ◽

Cell Subset ◽

B Cell Lymphoma ◽

Effector Memory ◽

T Cell Subset ◽

Progressive Growth

Abstract Allogeneic hematopoietic cell transplantation can be curative in patients with leukemia and lymphoma. However, progressive growth of malignant cells, relapse after transplantation, and graft-versus-host disease (GVHD) remain important problems. The goal of the current murine study was to select a freshly isolated donor T-cell subset for infusion that separates antilymphoma activity from GVHD, and to determine whether the selected subset could effectively prevent or treat progressive growth of a naturally occurring B-cell lymphoma (BCL1) without GVHD after recipients were given T cell–depleted bone marrow transplantations from major histocompatibility complex–mismatched donors. Lethal GVHD was observed when total T cells, naive CD4+ T cells, or naive CD8+ T cells were used. Memory CD4+CD44hi and CD8+CD44hi T cells containing both central and effector memory cells did not induce lethal GVHD, but only memory CD8+ T cells had potent antilymphoma activity and promoted complete chimerism. Infusion of CD8+ memory T cells after transplantation was able to eradicate the BCL1 lymphoma even after progressive growth without inducing severe GVHD. In conclusion, the memory CD8+ T-cell subset separated graft antilymphoma activity from GVHD more effectively than naive T cells, memory CD4+ T cells, or memory total T cells.

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Impaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type

10.1101/2021.09.15.21263652 ◽

2021 ◽

Author(s):

Robert B Lindell ◽

Donglan Zhang ◽

Jenny Bush ◽

Douglas C Wallace ◽

Joshua D Rabinowitz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Mitochondrial Function ◽

Cd4 T Cells ◽

Cell Activation ◽

Cytokine Production ◽

Cell Subset ◽

Immune Dysfunction ◽

Pediatric Sepsis

Background: Sepsis is the leading cause of death in hospitalized children worldwide. Despite its hypothesized immune-mediated mechanism, targeted immunotherapy for sepsis is not available for clinical use. Objective: To determine the association between cytometric, proteomic, bioenergetic, and metabolomic abnormalities and pathogen type in pediatric sepsis. Methods: Serial PBMC samples were obtained from 14 sepsis patients (34 samples) and 7 control patients for this pilot study. Flow cytometry was used to define immunophenotype, including T cell subset frequency and activation state, and assess intracellular cytokine production. Global immune dysfunction was assessed by TNF-α production capacity and monocyte HLA-DR expression. Mitochondrial function was assessed by bulk respirometry. Metabolites were measured by liquid chromatography-mass spectrometry. Results were compared by timepoint and pathogen type. For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org. Results: Sepsis patients were older and had higher illness severity compared to controls; demographics were otherwise similar. Compared to controls, sepsis patients demonstrated global immune dysfunction, loss of peripheral of non-naive CD4+ T cells, and reduced PBMC mitochondrial function. Metabolomic findings in sepsis patients were most pronounced at sepsis onset and included elevated uridine and 2-dehydrogluconate and depleted citrulline. Loss of peripheral non-naive CD4+ T cells was associated with immune dysfunction and reduced cytokine production despite increased T cell activation. CD4+ T cell differentiation and corresponding pro- and anti-inflammatory cytokines varied by pathogen. Conclusion: Pediatric sepsis patients exhibit a complex, dynamic physiologic state characterized by immunometabolic dysregulation which varies by pathogen type.

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Acute Gvhd Induce the Critical Depletion of Naïve Pool in Regulatory T Cells: Implication for Linked Pathogenesis into Chronic Gvhd

Blood ◽

10.1182/blood.v126.23.923.923 ◽

2015 ◽

Vol 126 (23) ◽

pp. 923-923

Author(s):

Takanori Yoshioka ◽

Yusuke Meguri ◽

Takeru Asano ◽

Yuriko Kishi ◽

Miki Iwamoto ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Immune Tolerance ◽

Cd4 T Cells ◽

Acute Gvhd ◽

Chronic Gvhd ◽

T Cell Subsets ◽

Effector Memory ◽

Ki 67

Abstract CD4+Foxp3+ regulatory T cells (Treg) play a central role in establishing immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). We previously reported that the long-term severe lymphopenia could result in the collapse of Treg homeostasis leading to the onset of chronic GVHD (Matsuoka et al. JCI 2010). We recently found that, not only in the chronic phase but also in the acute phase, the homeostasis of Treg is more susceptible to the post-transplant environment as compared to other lymphocyte subsets (Yoshioka et al. ASH 2014). However, the impact of acute GVHD on Treg homeostasis and the pathogenesis of following chronic GVHD has not been well studied. In this study, we examined Treg reconstitution in the early phase after transplant in patients with or without acute GVHD. For the purpose, we obtained peripheral blood samples at 2, 4, 8 and 12 weeks after transplant from 52 patients who received allogeneic HSCT, and then analyzed CD4+CD25med-highCD127lowFoxp3+ Treg comparing with CD4+CD25neg-lowCD127highFoxp3- conventional T cell (Tcon) and CD8+ T cells. CD4 T cell subsets are further divided into subpopulations by the expression of CD45RA and CD31. The expressions of Helios, Ki-67 and Bcl-2 on these subsets were also examined. After transplant, total lymphocyte counts in examined patients were significantly lower than the counts before the start of conditioning (median lymphocytes 95/ul at 2 weeks and 302/ul at 4 weeks vs 600/ul before conditioning, P<0.01 and P<0.01, respectively). As we reported before, Treg showed the active proliferation without diminishing Bcl-2 levels in the severe lymphopenia, resulted in the increased %Treg of CD4 T cells at 4 weeks after transplant (%Treg of CD4 T cells; 12.2% at 4 weeks, 4.6% in healthy controls, P<0.005). 18 patients who developed acute GVHD were studied Treg homeostasis before and after the onset of GVHD more in detail. Before the onset of acute GVHD, % Ki-67+ cells in Treg and Tcon were in the equivalent levels in these patients. After the onset of acute GVHD, % Ki-67+ cells in Treg was dramatically increased from 19.1% to 61.2% (median) and this was significantly higher than % Ki-67+ cells in Tcon after acute GVHD (P<0.05). %Treg of total CD4 T cells were significantly increased after GVHD (% Treg; Median 7.2% vs 12.2%, P<0.004). Expanded Treg after acute GVHD showed a predominant Helios+CD45RA-CD31- effector/memory phenotype with the lower level of Bcl-2 expression as compared to CD45RA+ naïve Treg. As a consequence, naïve Treg pool including CD45RA+CD31+ recent thymic emigrant Treg (RTE-Treg) were critically decreased during acute GVHD (%CD45RA+ cells; 12.7% into 6.5%, P<0.004: CD45RA+CD31+ cells; 3.6% into 2.1%, P<0.003). In contrast, Tcon still retained a relatively higher level of naïve pool (%CD45RA+ cells; 20.5%, % CD45RA+CD31+ cells; 10.9%) after acute GVHD. These data indicated that Treg proliferation was rapidly promoted in face with the inflammatory condition during acute GVHD and this appears to contribute the amelioration of developing GVHD. However, the prompt reaction resulted in the depletion of naïve Treg pool which is important to maintain stable Treg homeostasis in the long period. In conclusion, our findings suggest that acute GVHD drives aggressive Treg proliferation resulting in the increased percentage of this subset but this also induce the severe alteration of Treg homeostasis by depleting naïve Treg, which may provide the linked pathogenesis of the subsequent onset of chronic GVHD. The careful monitoring of Treg from the point of view might provide important information to promote immune tolerance. Disclosures No relevant conflicts of interest to declare.

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Somatic Mutations in Clonally Expanded T-lymphocytes in Patients with Chronic Graft-Versus-Host Disease

10.1101/747196 ◽

2019 ◽

Author(s):

Giljun Park ◽

Daehong Kim ◽

Jani Huuhtanen ◽

Sofie Lundgren ◽

Rajiv K. Khajuria ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Cd4 T Cells ◽

Somatic Mutations ◽

Chronic Gvhd ◽

Sensitivity Testing ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host

ABSTRACTGraft-versus-host-disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation. GvHD patients have aberrant T cell expansions, which are thought to drive pathological immune activation. Here we report mechanistic insights that somatic mutations may account for persistent clonal T cell expansions in chronic GvHD (cGvHD). In an index patient suffering from cGVHD, we discovered persisting somatic MTOR, NFKB2, and TLR2 mutations in an expanded CD4+ T clone. In the screening cohort (n=135), the MTOR P2229R kinase domain mutation was detected in two additional cGvHD patients, but not in controls. Functional analysis of the discovered MTOR mutation indicated a gain-of-function alteration in translational regulation yielding in up-regulation of phosphorylated S6K1, S6, and AKT. Paired single-cell RNA and T cell receptor alpha and beta sequencing strongly supported cytotoxicity and abnormal proliferation of the clonally expanded CD4+ T cells. Real-time impedance measurements indicated increased cytotoxicity of mutated CD4 + T cells against the patient’s fibroblasts. High throughput drug-sensitivity testing suggested that mutations induce resistance to mTOR inhibitors but increase sensitivity for HSP90 inhibitors. Our findings suggest a novel explanation for the aberrant, persistent T cell activation in cGvHD, and pave the way for novel targeted therapies.

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Reconstitution of Regulatory T Cell Subpopulations After Allogeneic Hematopoietic Stem Cell Transplantation and Graft-Versus-Host-Disease

Blood ◽

10.1182/blood.v120.21.1948.1948 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1948-1948

Author(s):

Alienor Xhaard ◽

Helene Moins ◽

Marc Busson ◽

Maryvonnick Carmagnat ◽

Marie Robin ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

T Cell ◽

Malignant Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cd4 T Cell ◽

Effector Memory ◽

Hematopoietic Stem ◽

Graft Versus Host

Abstract Abstract 1948 Previous studies on the reconstitution of regulatory T cells (Treg) after allogeneic hematopoietic stem cell transplantation (HSCT) have shown a delayed reconstitution in patients (pts) with acute graft-versus-host-disease (GvHD) (Magenau, 2010) and an association between impaired Treg reconstitution and the development of extensive chronic GvHD (Matsuoka, 2010). However, no studies have analyzed naive (nTreg) versus memory (mTreg) Treg reconstitution in a longitudinal cohort with large numbers of pts. From 2006 to 2009, 165 consecutive pts were prospectively analyzed in our center post-HSCT. Fresh whole blood samples were obtained 3 (n=155), 6 (n=162), 12 (n=165) and 24 (n=94) months after HSCT and analyzed by flow cytometry to quantify CD4 T cells, including naive, activated, central memory and effector memory subsets (Sallusto, 1999), as well as Treg (CD4+ CD25+ CD127neg/lo), including nTreg (CD45RA+) and mTreg (CD45RAneg). The results are presented as median values of circulating cells. Median age was 41 years (range: 6–68). The indication for HSCT was malignant disease in 92%. The conditioning regimen was reduced-intensity (RIC) in 51%. The donor was an HLA-identical sibling in 56%. The source of stem cells was peripheral blood (PBSC), bone marrow (BM) and cord blood (CB) in 65%, 28% and 7%, respectively. All pts received cyclosporine as GvHD prophylaxis. GvHD was defined as acute if occurring before day 100 and chronic thereafter. Total Treg (tTreg) increased from 13/μL at 3 months to 44/μL at 24 months, but always remained inferior to healthy controls (HC) (66/μL). nTreg increased from 1.8/μL at 3 months to 4.8/μL at 24 months (HC: 24/μL). mTreg increased from 10.7/μL at 3 months to 33.3/μL at 24 months (HC: 42/μL). The CD4/Treg ratio remained stable at 12.6 at 3 months and 11.6 at 24 months while the nCD4/nTreg ratio increased from 17.4 at 3 months to 42.7 at 24 months, showing a larger expansion of naive cells in the CD4 T cell compartment than in the Treg compartment (Figure 1) and a larger expansion of memory cells in the Treg than within the CD4 cells. At 3 months post-HSCT, tTreg, nTreg and mTreg were significantly higher in PBSC recipients (18.4, 2.7 and 14.5/μL) than in BM (8.1, 0.9 and 6.5/μL) and CB recipients (6.5, 0.6 and 5.3/μL) (p=0.0001), respectively. Pts transplanted after a RIC regimen had significantly more tTreg and mTreg than pts transplanted after a standard regimen (17 and 14/μL, compared with 9.8 and 8/μL, p=0.004 and 0.008 respectively). Pts transplanted for an aplastic anemia had significantly fewer nTreg than pts transplanted for a malignant disease (0.4 and 1.9/μL, p=0.001). At 6 months post-HSCT, tTreg, nTreg and mTreg were significantly higher (p=≤0.01) in pts transplanted from an HLA-identical sibling (19.5, 1.9 and 17.2/μL) compared with pts transplanted from an unrelated donor (13.2, 1.2 and 11/μL). At 12 and 24 months post-HSCT, younger pts (≤15 years) had significantly more nTreg than older pts (9.8 and 28.7/μL compared with 2.1 and 4.2, p=0.001). In pts with previous acute GvHD, tTreg and mTreg were significantly lower at 3 (8.5 and 7.7/μL) and 6 months (14.6 and 12.5/μL) compared with pts without (15.6 and 13.8/μL at 3 months, p=0.005 and 21.3 and 18.2/μL at 6 months, p≤0.007), respectively. Absolute numbers of tTreg, nTreg and mTreg, and the frequencies of Treg relative to activated, effector memory and central memory CD4 T cells at 3, 6 and 12 months post-HSCT did not predict the occurrence of a later episode of chronic GvHD up to 2 years post-HSCT. In our population, total, naive and memory Treg reconstitution was delayed post-HSCT and remained below the normal range up to 2 years after HSCT. tTreg reconstitution post-HSCT was mostly due to mTreg expansion. RIC regimen and PBSC as source of stem cells were associated with a better short-term reconstitution. At 6 months, pts transplanted from siblings had a better reconstitution while nTreg long-term reconstitution was mainly influenced by recipient age (better if ≤15 years). While previous acute GvHD impaired Treg reconstitution, Treg subsets (absolute numbers and frequencies relative to CD4 T cell subsets) at 3, 6 and 12 months post-HSCT were unable to predict chronic GvHD in this large cohort of patients. We believe these data are of particular interest regarding the recently increasing number of Treg interventional studies in humans in the context of HSCT. Disclosures: No relevant conflicts of interest to declare.

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A Critical Role of MyD88 Signaling in Donor T Cells for Graft-Versus-Host Disease (GVHD) and Graft-Versus-Leukemia Effect (GVL) After Experimental Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

Blood ◽

10.1182/blood.v120.21.1893.1893 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1893-1893

Author(s):

Ji-Young Lim ◽

Dae-Chul Jeong ◽

Hyewon Youn ◽

Eun-Young Choi ◽

Chang-Ki Min

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Critical Role ◽

Hematopoietic Stem ◽

Donor T Cells ◽

Myd88 Signaling

Abstract Abstract 1893 The therapeutic potential of allogeneic hematopoietic stem cell transplantation (allo-HSCT) relies on the graft-versus-leukemia effect (GVL) to eradicate residual tumor cells by immunologic mechanisms. However, graft-versus-host disease (GVHD) remains the major toxicity of allo-HSCT. Alloreactive donor T cells are important effector cells in the development of GVHD, and proinflammatory cytokines enhance the generation of donor antihost cytotoxic function. Myeloid differentiation factor (MyD88) is a cytoplasmic adaptor molecule essential for integrating and transducing the signals generated by the Toll-like receptor (TLR) family. TLR engagement on professional antigen-presenting cells induces their maturation, resulting in optimal T-cell activation. However, recent advances indicate that the adjuvant effects of certain TLR agonists may also be attributed to the activation of TLRs and MyD88 directly in T cells. Both CD4 and CD8 T cells express functional TLRs. It remains to be defined whether direct TLR signaling on donor T cells is critical for GVHD or GVL activity. We used C57BL/6 (H-2b) → B6D2F1 (H-2b/d) experimental allo-HSCT model, which differs at major and minor histocompatibility loci, to address the role of donor T cell MyD88 signaling on GVHD and GVL. Lethally irradiated recipient mice were transplanted TCD-BM (5 × 106) together with either wild-type (WT) or MyD88 knock out (KO) mice spleen T cells (1 × 106) on day 0 and then host-type P815 mastocytoma or L1210 leukemia (H-2d) cells were injected either intravenously (3 × 103) or subcutaneously (1 × 106) on day 1 to generate a GVHD/GVL model. First of all, clinical GVHD scores were comparable between recipients of WT T cells and MyD88 KO T cells. At 70 days post-allo-HSCT, 50 % of allogeneic recipients of WT T cells died due to severe GVHD, but necropsy showed no evidence of tumor. In contrast, 83.5% of those of MyD88 KO T cells died with gross evidence of tumors (P<.05). Moreover, subcutaneous tumors in the allogeneic recipients receiving MyD88 KO T cells exhibited markedly increased growth in vivo compared to those receiving WT T cells (tumor volume on day 41, 15205.6 vs. 373.9 mm3, P<.01). GVHD mortality is critically dependent on donor CD4 T cells in this donor/recipient strain combination (B6 → B6D2F1) and CD8 T cells that mediate cytotoxicity are more potent effectors of GVL. The percentages of donor T cells to undergo proliferation or apoptosis in response to alloantigens in vivo between the two T cell types was examined; apoptosis of CD8 T cells in recipients of MyD88 KO T cells was significantly enhanced compared to those of WT T cell recipients (P<.01) whereas apoptosis of CD4 T cells was comparable between two groups. Resultingly, the percentages of CD8 T cells in recipients of MyD88 KO T cells were significantly lower (P<.01). We next examined the effects of MyD88 signaling in donor T cells on cytolytic activity to host antigens. Splenocytes harvested from WT mice showed stronger cytolytic activity against P815 targets compared to those from MyD88 KO mice (P<.01). After allogeneic mixed leukocyte reaction, responder T cells from MyD88 KO mice showed markedly reduced IFN-γ, MCP-1 and IL-17A production with a significant augmentation in IL-10 secretion. We further evaluated the effect of T-cell MyD88 deficiency on GVL mediated by the intensity of total body irradiation (TBI) conditioning (1300 vs. 900 cGy, Exp Hematol 2011; 39: 1018–29). Enhanced GVL in the allogeneic recipients receiving 1300 cGy TBI was not shown in the recipients of MyD88 KO T cells. In summary, these results highlight a critical role for MyD88 signaling in T-cell activation and cytotoxicity, offering the opportunity for improving GVL activity by targeting TLR-MyD88 signaling within donor T cells. Furthermore, these data demonstrated that MyD88 deficiency in T cells can impair cytolytic function or subsequent GVL activity of CD8 T cells without significant change in the severity of CD4-dependent GVHD. This difference is attributed to the fact that MyD88 deficiency in T cells causes an enhanced apoptosis of donor CD8 T cells but not donor CD4 T cells in vivo after HSCT. Disclosures: No relevant conflicts of interest to declare.

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Probiotic supplementation reduces inflammatory profiles but does not prevent oral immune perturbations during SIV infection

Scientific Reports ◽

10.1038/s41598-021-93918-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rhianna Jones ◽

Kyle Kroll ◽

Courtney Broedlow ◽

Luca Schifanella ◽

Scott Smith ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Rhesus Macaques ◽

Oral Microbiome ◽

Probiotic Supplementation ◽

Siv Infection ◽

Anti Inflammatory

AbstractHIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections.

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Upregulation of PD-1 expression on circulating CD8+ but not CD4+ T cells is associated with tuberculosis infection in health care workers

BMC Immunology ◽

10.1186/s12865-021-00433-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Cui-lin Shi ◽

Jian-ping Zhang ◽

Ping Xu ◽

Jin Li ◽

Jie Shen ◽

...

Keyword(s):

Health Care ◽

T Cells ◽

T Cell ◽

Health Care Workers ◽

Cd4 T Cells ◽

Receptor Expression ◽

Effector Memory ◽

Care Workers ◽

Latent Tb ◽

Latent Tb Infection

Abstract Background Health care workers (HCWs) are at risk for occupationally acquired Mycobacterium tuberculosis infection and tuberculosis (TB) disease due to repeated exposure to workplace tubercle bacilli. To determine whether continual mycobacterial stimulation correlates with increased expression of inhibitory T cell receptors, here we compared PD-1 receptor expression on surfaces of circulating T cells between naïve (uninfected) HCWs and HCWs with latent TB infection (LTBI). Result Data collected from 133 medical workers who met study selection criteria were included in the final analysis. QuantiFERON-TB Gold In-Tube (QFT-GIT) testing yielded positive results for 32 HCWs, for an overall LTBI rate of 24.1%. Multivariate analysis identified HCW length of service > 15 years as an independent risk factor for a positive QFT-GIT result. In addition, comparisons of blood T cell subgroup profiles between QFT- and QFT+ groups indicated QFT+ subjects possessed greater proportions of mature (TM), transitional memory (TTM) and effector memory (TEM) CD4+ T cell subgroups and lower proportions of naïve T cells (TN). Moreover, the QFT+ group percentage of CD8+ T cells with detectable surface PD-1 was significantly higher than the corresponding percentage for the QFT- group. Meanwhile, no statistical intergroup difference was observed in percentages of CD4+ T cells with detectible surface PD-1. Conclusions Our data demonstrated that upregulated PD-1 expression on circulating CD8+, but not CD4+ T cells, was associated with latent TB infection of HCWs. As compared to other hospitals, occupational TB infection risk in our hospital was substantially mitigated by implementation of multitiered infection control measures.

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VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance

Science ◽

10.1126/science.aay0524 ◽

2020 ◽

Vol 367 (6475) ◽

pp. eaay0524 ◽

Cited By ~ 22

Author(s):

Mohamed A. ElTanbouly ◽

Yanding Zhao ◽

Elizabeth Nowak ◽

Jiannan Li ◽

Evelien Schaafsma ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Subset ◽

Peripheral Tolerance ◽

Cell Immune Response ◽

Naive T Cells ◽

Naïve T Cells ◽

Naïve T Cell ◽

Naive T Cell

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

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