scholarly journals Immunization of Vγ2Vδ2 T cells programs sustained effector memory responses that control tuberculosis in nonhuman primates

2019 ◽  
Vol 116 (13) ◽  
pp. 6371-6378 ◽  
Author(s):  
Ling Shen ◽  
James Frencher ◽  
Dan Huang ◽  
Wandang Wang ◽  
Enzhuo Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Nonhuman Primates ◽  
Effector T Cells ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Lung Pathology ◽  
Ifn Γ ◽  
Critical Components ◽  
Vγ2vδ2 T Cells ◽  
Fast Acting

Tuberculosis (TB) remains a leading killer among infectious diseases, and a better TB vaccine is urgently needed. The critical components and mechanisms of vaccine-induced protection againstMycobacterium tuberculosis(Mtb) remain incompletely defined. Our previous studies demonstrate that Vγ2Vδ2 T cells specific for (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) phosphoantigen are unique in primates as multifunctional effectors of immune protection against TB infection. Here, we selectively immunized Vγ2Vδ2 T cells and assessed the effect on infection in a rhesus TB model. A single respiratory vaccination of macaques with an HMBPP-producing attenuatedListeria monocytogenes(LmΔactA prfA*) caused prolonged expansion of HMBPP-specific Vγ2Vδ2 T cells in circulating and pulmonary compartments. This did not occur in animals similarly immunized with an LmΔgcpEstrain, which did not produce HMBPP. LmΔactA prfA* vaccination elicited increases in Th1-like Vγ2Vδ2 T cells in the airway, and induced containment of TB infection after pulmonary challenge. The selective immunization of Vγ2Vδ2 T cells reduced lung pathology and mycobacterial dissemination to extrapulmonary organs. Vaccine effects coincided with the fast-acting memory-like response of Th1-like Vγ2Vδ2 T cells and tissue-resident Vγ2Vδ2 effector T cells that produced both IFN-γ and perforin and inhibited intracellular Mtb growth. Furthermore, selective immunization of Vγ2Vδ2 T cells enabled CD4+and CD8+T cells to mount earlier pulmonary Th1 responses to TB challenge. Our findings show that selective immunization of Vγ2Vδ2 T cells can elicit fast-acting and durable memory-like responses that amplify responses of other T cell subsets, and provide an approach to creating more effective TB vaccines.

scholarly journals Phosphoantigen-activated Vγ2Vδ2 T cells antagonize IL-2–induced CD4+CD25+Foxp3+ T regulatory cells in mycobacterial infection

Blood ◽  
2009 ◽  
Vol 113 (4) ◽  
pp. 837-845 ◽  
Author(s):  
Guangming Gong ◽  
Lingyun Shao ◽  
Yunqi Wang ◽  
Crystal Y. Chen ◽  
Dan Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treatment Regimen ◽  
T Regulatory Cells ◽  
Mycobacterial Infection ◽  
T Cell Subsets ◽  
Regulatory Cells ◽  
Ifn Γ ◽  
Vγ2vδ2 T Cells

Abstract Although Foxp3+ T regulatory cells (Tregs) are well documented for their ability to suppress various immune cells, T-cell subsets capable of counteracting Tregs have not been demonstrated. Here, we assessed phosphoantigen-activated Vγ2Vδ2 T cells for the ability to interplay with Tregs in the context of mycobacterial infection. A short-term IL-2 treatment regimen induced marked expansion of CD4+CD25+Foxp3+ T cells and subsequent suppression of mycobacterium-driven increases in numbers of Vγ2Vδ2 T cells. Surprisingly, activation of Vγ2Vδ2 T cells by adding phosphoantigen Picostim to the IL-2 treatment regimen down-regulated IL-2–induced expansion of CD4+CD25+Foxp3+ T cells. Consistently, in vitro activation of Vγ2Vδ2 T cells by phosphoantigen plus IL-2 down-regulated IL-2–induced expansion of CD4+CD25+Foxp3+ T cells. Interestingly, anti–IFN-γ–neutralizing antibody, not anti–TGF-β or anti–IL-4, reduced the ability of activated Vγ2Vδ2 T cells to down-regulate Tregs, suggesting that autocrine IFN-γ and its network contributed to Vγ2Vδ2 T cells' antagonizing effects. Furthermore, activation of Vγ2Vδ2 T cells by Picostim plus IL-2 treatment appeared to reverse Treg-driven suppression of immune responses of phosphoantigen-specific IFNγ+ or perforin+ Vγ2Vδ2 T cells and PPD-specific IFNγ+αβ T cells. Thus, phos-phoantigen activation of Vγ2Vδ2 T cells antagonizes IL-2–induced expansion of Tregs and subsequent suppression of Ag-specific antimicrobial T-cell responses in mycobacterial infection.

scholarly journals Mycobacteria-specific CD4+IFN-γ+ cell expresses naïve-surface markers and confers superior protection against tuberculosis infection compared to central and effector memory CD4+ T cell subsets

2018 ◽  
Author(s):  
Jinyun Yuan ◽  
Janice Tenant ◽  
Thomas Pacatte ◽  
Christopher Eickhoff ◽  
Azra Blazevic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Vaccine Trial ◽  
Memory Cell ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Surface Markers ◽  
Activation Markers ◽  
Ifn Γ

AbstractFailure of the most recent tuberculosis (TB) vaccine trial to boost BCG mediated anti-TB immunity despite highly durable Th1-specific central (TCM) and effector (TEM) memory cell responses, highlights the importance of identifying optimal T cell targets for protective vaccines. Here we describe a novel, Mycobacterium tuberculosis (Mtb)-specific IFN-γ+CD4+ T cell population expressing surface markers characteristic of naïve T cells (TNLM), that were induced in both human (CD45RA+CCR7+CD27+CD95-) and murine (CD62L+CD44-Sca-1+CD122-) systems in response to mycobacteria. In BCG vaccinated subjects and those with latent TB infection, TNLM cells, compared to bonafide naïve CD4+ T cells were identified by absence of CD95 expression and had increased expression CCR7 and CD27, the activation markers T-bet, CD69 and PD-1 and the survival marker CD74. Increased TNLM frequencies were noted in the lung and spleen of wild type C57BL6 mice at 2 weeks after infection with Mtb, and progressively decreased at later time points, a pattern not seen in TNF-α+CD4+ T cells expressing naïve cell surface markers. Importantly, adoptive transfer of highly purified TNLM from vaccinated ESAT-61-20-specific TCR transgenic mice conferred superior protection against Mtb infection in Rag-/- mice when compared with total meory populations (central and effector memory cells). Thus, TNLM cells may represent a memory T cell population that if optimally targeted may significantly improve future TB vaccine responses.

scholarly journals Interplay between IL-10, IFN-γ, IL-17A and PD-1 Expressing EBNA1-Specific CD4+ and CD8+ T Cell Responses in the Etiologic Pathway to Endemic Burkitt Lymphoma

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5375
Author(s):  
Catherine S. Forconi ◽  
David H. Mulama ◽  
Priya Saikumar Lakshmi ◽  
Joslyn Foley ◽  
Juliana A. Otieno ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Burkitt Lymphoma ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Healthy Children ◽  
Ifn Γ

Children diagnosed with endemic Burkitt lymphoma (eBL) are deficient in interferon-γ (IFN-γ) responses to Epstein–Barr Nuclear Antigen1 (EBNA1), the viral protein that defines the latency I pattern in this B cell tumor. However, the contributions of immune-regulatory cytokines and phenotypes of the EBNA1-specific T cells have not been characterized for eBL. Using a bespoke flow cytometry assay we measured intracellular IFN-γ, IL-10, IL-17A expression and phenotyped CD4+ and CD8+ T cell effector memory subsets specific to EBNA1 for eBL patients compared to two groups of healthy children with divergent malaria exposures. In response to EBNA1 and a malaria antigen (PfSEA-1A), the three study groups exhibited strikingly different cytokine expression and T cell memory profiles. EBNA1-specific IFN-γ-producing CD4+ T cell response rates were lowest in eBL (40%) compared to children with high malaria (84%) and low malaria (66%) exposures (p < 0.0001 and p = 0.0004, respectively). However, eBL patients did not differ in CD8+ T cell response rates or the magnitude of IFN-γ expression. In contrast, eBL children were more likely to have EBNA1-specific CD4+ T cells expressing IL-10, and less likely to have polyfunctional IFN-γ+IL-10+ CD4+ T cells (p = 0.02). They were also more likely to have IFN-γ+IL-17A+, IFN-γ+ and IL-17A+ CD8+ T cell subsets compared to healthy children. Cytokine-producing T cell subsets were predominantly CD45RA+CCR7+ TNAIVE-LIKE cells, yet PD-1, a marker of persistent activation/exhaustion, was more highly expressed by the central memory (TCM) and effector memory (TEM) T cell subsets. In summary, our study suggests that IL-10 mediated immune regulation and depletion of IFN-γ+ EBNA1-specific CD4+ T cells are complementary mechanisms that contribute to impaired T cell cytotoxicity in eBL pathogenesis.

Human CMVpp65-Specific Stem Cell-like Memory T-Cells (TSCM) Are a Principal Source for Rapid Repopulation of Immunodominant Central Memory (TCM) and Effector Memory (TEM) in the Circulation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5728-5728
Author(s):  
Tzu-Yun Kuo ◽  
Aisha Hasan ◽  
Manuel Guerreiro ◽  
Richard J. O'Reilly
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Amino Acid Sequences ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Tnf Α ◽  
Artificial Antigen ◽  
Ifn Γ ◽  
Antigen Presenting

Abstract Latent CMV infection is controlled by a limited repertoire of immunodominant T-cells specific for viral peptides, particularly CMVpp65 and CMV IE-1. The antigen-specific T-cell subsets responsible for maintaining memory T-cells in this repertoire and repopulating them in response to periodic viral reactivations remain unclear. In this study, we generated T-cells specific for CMVpp65 from naïve (TN), TSCM, TCM and TEM subsets isolated from the blood of HLA-A*0201 normal seropositive donors and then comparatively characterized NLV-HLA-A*0201 Tetramer+ T-cells from each of these subsets. Following in vitro sensitization with artificial antigen-presenting cells transduced to express HLA-A*0201 and CMVpp65 and expansion with IL-7, IL-15 and IL-2, Tet+ T-cells were regularly generated from CD62L+CD45RO-CD95- TN and from CD62L+CD45RO-CD95+ TSCM, as well as TCM and TEM. Isolated Tet+ TN, TSCM, TCM and TEM were each able to generate IFN-γ, TNF-α and granzyme B. Each Tet+ subset also expressed similar level of PD-1 and KLRG-1. However, Tet+ TN and TSCM expressed higher levels of CD27 and lower levels of CD57 than TCM or TEM. Tet+ TSCM were distinguished from Tet+ TN, TCM and TEM by a significantly greater level of proliferation and by their rapid and selective expansion of NLV-specific T-cells bearing TCRs identical by amino acid sequences to those expressed by TEM and TCM in the blood. Thus, Tet+ TSCM rather than Tet+ TN constitute the principal repertoire for repopulation of immunodominant memory T-cells sustained in the circulation. Disclosures Hasan: Atara: Patents & Royalties.

Identification of Tigit on Intra-Tumor T Cells As a New Target for Immune Checkpoint Blockade in Follicular Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 917-917 ◽  
Author(s):  
Sarah Gothberg ◽  
Kanutte Huse ◽  
Arne Kolstad ◽  
Ole Christian Lingjærde ◽  
Bjørn Østenstad ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Checkpoint Blockade ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Cytokine Signaling ◽  
Ifn Γ ◽  
Checkpoint Receptors

Abstract Background: Follicular lymphoma (FL) is the most common subtype of indolent non Hodgkin's lymphoma (NHL). Median survival is long (>10 years), but current chemo-immunotherapy regimens used for FL are usually not curative. While T cells in the FL tumor microenvironment are considered dysfunctional and associated with disease progression, a better understanding of T-cell signaling may reveal how to productively engage tumor-infiltrating T cells to kill lymphoma B cells. Our previous study showed that expression of the immune checkpoint receptor PD-1 was directly correlated with reduced cytokine signaling in FL T cells (Myklebust et al., Blood 2013). Antibody immunotherapy targeting the PD-1/PD-L1 pathway has shown significant activity in solid tumors, but these benefits have not been as profound in NHLs, including FL. Co-blockade of checkpoint inhibitors may therefore be necessary to generate optimal anti-tumor responses in FL. The hypothesis underlying this study was that characterizing signaling responses in FL tumor-infiltrating T cells will identify new targets for combination of checkpoint blockade. Methods: Surface expression of 9 checkpoint receptors governing T cell function was measured in subsets of CD4 and CD8 T cells from FL lymph node tumors (n = 14) and from healthy donor tonsils (n= 11) and peripheral blood samples (n = 7) using fluorescence flow cytometry. Patterns of checkpoint receptor expression were compared with 1) intracellular phospho-protein signaling response and 2) cytokine production for subsets of T cells infiltrating FL tumors and the corresponding T-cell populations in healthy tonsils. Phospho-specific flow cytometry measured phosphorylation of STATs and T cell receptor (TCR) signaling effectors within minutes following stimulation by IL-4, IL-7, IL-21, or α-CD3+α-CD28 (TCR stimulation) antibodies. Results: CD4 and CD8 T cells infiltrating FL tumors were gated into subsets defined by PD-1 and ICOS protein expression, and compared to cognate T cell subsets in healthy tonsils. FL and tonsil T cells closely matched in their signaling responses to IL-4, IL-7, and IL-21 stimulation, with PD-1 expressing cells (CD4+PD-1hiICOS+ (TFH) and CD8+PD-1int T cells) exhibiting modest phospho-protein signaling responses compared to T cells not expressing PD-1. Furthermore, TCR membrane proximal signaling events (p-CD3ζ, p-SLP76) following TCR stimulation were comparable in FL and tonsil T cells. This contrasted reduced phospho-ERK signaling in all CD4 and CD8 T cell subsets infiltrating FL tumors which distinguished them from tonsillar T cells. IFN-γ production also differed between FL and tonsils, as CD8 T cells infiltrating FL tumors produced less IFN-γ. Reduced IFN-γ production was independent of PD-1 expression, suggesting suppressed function in these T cells which could be due to inhibitory receptors other than PD-1. Of the 9 checkpoint receptors measured, PD-1 and T cell Ig and ITIM domain (TIGIT) were expressed at the highest frequency. In FL, TIGIT was expressed in 58% and 80% of CD8 effector and effector memory cells, respectively, as compared to 43% and 68% of the cognate healthy tonsillar subsets. TIGIT was also frequently expressed in CD4 FL T cells, as 52% and 79% of effector and effector memory cells expressed TIGIT, respectively, as compared to 16% and 59% of the corresponding subsets from healthy tonsils. viSNE analysis demonstrated that TIGIT and PD-1 were frequently co-expressed in FL T cells, and a large fraction of PD-1int T cells had high expression of TIGIT (Figure 1). These results provide a rationale for co-blockade of PD-1 and TIGIT in FL and for investigation of how co-blockade impacts T cell functions. Conclusions: These results reveal specific suppression of cytokine signaling in CD8 effector T cells infiltrating FL tumors and identify TIGIT and PD-1 as strong candidates for co-checkpoint blockade in FL. A deeper understanding of the interplay between checkpoint receptors and key T cell cytokine signaling events in FL will further assist in engineering immuno-therapeutic regiments that improve FL patient clinical outcomes. Disclosures Kolstad: Nordic Nanovector: Other: Membership of Scientific Advisory Board. Levy:Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding. Irish:Incyte: Research Funding; Janssen: Research Funding; Cytobank, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Ex Vivo Kinetics of Early and Long-Term Multifunctional Human Leukocyte Antigen E-Specific CD8+ Cells in Volunteers Immunized with the Ty21a Typhoid Vaccine

2010 ◽  
Vol 17 (9) ◽  
pp. 1305-1314 ◽  
Author(s):  
Rosângela Salerno-Goncalves ◽  
Rezwanul Wahid ◽  
Marcelo B. Sztein
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Typhoid Vaccine ◽  
Tnf Α ◽  
Ifn Γ ◽  
Kinetics Of

ABSTRACT T cells are likely to play an important role in the host defense against Salmonella enterica serovar Typhi, the causative agent of typhoid fever. We have shown that HLA-E can function as a restriction element for S. Typhi-specific CD8+ T cells. Because of the potential importance of HLA-E-restricted CD8+ responses in resistance to Salmonella infection, we characterized these responses and investigated their kinetics of appearance and persistence in volunteers immunized orally with the licensed attenuated Ty21a strain typhoid vaccine. Cells were obtained from volunteers before and at days 2, 4, 7, 10, 14, 28, 42, 56, 120, 180, 360, and 720 after immunization. An ex vivo multicolor staining panel including antibodies to CD107a and -b, interleukin-2, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α) was used to functionally assess memory T-cell subsets by flow cytometry. Increases in cytokine-secreting CD8+ cells were observed in the T effector/memory (TEM) and CD45RA+ TEM (TEMRA) subsets as early as 4 days after immunization and persisted, particularly in the TEMRA subset, up to 2 years after immunization. The majority of HLA-E-restricted CD8+ cells 28 to 56 days after immunization coexpressed CD107, IFN-γ, and TNF-α, showing characteristic features of multifunctional T cells. In summary, the multifunctionality and longevity of the HLA-E-restricted CD8 responses observed in this study highlight their significance in adaptive immunity to S. Typhi. Finally, this is the first demonstration, in either animals or humans, of the presence of long-term multifunctional HLA-E-restricted CD8+ cells after immunization.

scholarly journals The Relative Importance of T Cell Subsets in Immunity and Immunopathology of Airborne Mycobacterium tuberculosis Infection in Mice

2001 ◽  
Vol 193 (3) ◽  
pp. 271-280 ◽  
Author(s):  
Tirsit Mogues ◽  
Mariam E. Goodrich ◽  
Lynn Ryan ◽  
Ronald LaCourse ◽  
Robert J. North
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Class Ii ◽  
T Cell Subsets ◽  
Cell Mediated Immunity ◽  
Lung Pathology ◽  
Ifn Γ ◽  
Stationary Level ◽  
Αβ T Cells

Wild-type (WT) and targeted-mutant mice incapable of making αβ T cells, γδ T cells, class I major histocompatibility complex (MHC), class II MHC, interferon (IFN)-γ, or inducible nitric oxide synthase (NOS2), were infected with Mycobacterium tuberculosis (Mtb) by aerosol, and monitored over time for their ability to (a) control infection, (b) develop histopathology at sites of infection, and (c) survive. WT mice acquired the ability to control and to hold infection at a stationary level from day 20 on. This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-γ and NOS2 mRNA, and with an median survival time (MST) of 258.5 d. In the absence of αβ T cells, Mtb grew progressively and rapidly to induce a necrotic, neutrophil-dominated lung pathology that killed mice with an MST of 48 d. In the absence of CD4-mediated immunity (class II−/− mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d. By contrast, in the absence of CD8 T cell–mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.

CD4+CD25- effector T cells from healthy controls and MS patients do not differ in mRNA expression of IFN-γ, IL-2, and TNF-α

2004 ◽  
Vol 31 (S 1) ◽  
Author(s):  
A Hug ◽  
J Haas ◽  
A Viehöver ◽  
B Fritz ◽  
B Storch-Hagenlocher ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Effector T Cells ◽  
Healthy Controls ◽  
Tnf Α ◽  
Ifn Γ

scholarly journals Cryopreservation of Whole Tumor Biopsies from Rectal Cancer Patients Enable Phenotypic and In Vitro Functional Evaluation of Tumor-Infiltrating T Cells

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2428
Author(s):  
Frank Liang ◽  
Azar Rezapour ◽  
Peter Falk ◽  
Eva Angenete ◽  
Ulf Yrlid
Keyword(s):  
Rectal Cancer ◽  
T Cells ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Functional Evaluation ◽  
Mait Cells ◽  
Ifn Γ ◽  
Tumor Biopsies

TILs comprise functionally distinct conventional and unconventional T cell subsets and their role in responses to CRC treatments is poorly understood. We explored recovery of viable TILs from cryopreserved tumor biopsies of (chemo)-radiated patients with rectal cancer to establish a platform for retrospective TIL analyses of frozen tumors from pre-selected study cohorts. Frequencies of TIL subsets and their capacity to mount IFN-γ responses in cell suspensions of fresh vs. cryopreserved portions of the same tumor biopsies were determined for platform validation. The percentages and proportions of CD4+ TILs and CD8+ cytotoxic T lymphocytes (CTLs) among total TILs were not affected by cryopreservation. While recovery of unconventional γδ T cells and mucosal-associated invariant T cells (MAIT cells) was stable after cryopreservation, the regulatory T cells (Tregs) were reduced, but in sufficient yields for quantification. IFN-γ production by in vitro-stimulated CD4+ TILs, CTLs, γδ T cells, and MAIT cells were proportionally similar in fresh and cryopreserved tumor portions, albeit the latter displayed lower levels. Thus, the proposed platform intended for TIL analyses on cryopreserved tumor biobank biopsies holds promises for studies linking the quantity and quality of TIL subsets with specific clinical outcome after CRC treatment.

scholarly journals Lactobacillus reuteri DSM 17938 differentially modulates effector memory T cells and Foxp3+ regulatory T cells in a mouse model of necrotizing enterocolitis

2014 ◽  
Vol 307 (2) ◽  
pp. G177-G186 ◽  
Author(s):  
Yuying Liu ◽  
Dat Q. Tran ◽  
Nicole Y. Fatheree ◽  
J. Marc Rhoads
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Necrotizing Enterocolitis ◽  
Lactobacillus Reuteri ◽  
Intestinal Inflammation ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Mesenteric Lymph Nodes ◽  
Mesenteric Lymph

Necrotizing enterocolitis (NEC) is an inflammatory disease with evidence of increased production of proinflammatory cytokines in the intestinal mucosa. Lactobacillus reuteri DSM 17938 (LR17938) has been shown to have anti-inflammatory activities in an experimental model of NEC. Activated effector lymphocyte recruitment to sites of inflammation requires the sequential engagement of adhesion molecules such as CD44. The phenotype of CD44+CD45RBlo separates T effector/memory (Tem) cells from naive (CD44−CD45RBhi) cells. It is unknown whether these Tem cells participate in the inflammation associated with NEC and can be altered by LR17938. NEC was induced in 8- to 10-day-old C57BL/6J mice by gavage feeding with formula and exposure to hypoxia and cold stress for 4 days. Survival curves and histological scores were analyzed. Lymphocytes isolated from mesenteric lymph nodes and ileum were labeled for CD4, CD44, CD45RB, intracellular Foxp3, and Helios and subsequently analyzed by flow cytometry. LR17938 decreased mortality and the incidence and severity of NEC. The percentage of Tem cells in the ileum and mesenteric lymph nodes was increased in NEC but decreased by LR17938. Conversely, the percentage of CD4+Foxp3+ regulatory T (Treg) cells in the intestine decreased during NEC and was restored to normal by LR17938. The majority of the Treg cells preserved by LR17938 were Helios+ subsets, possibly of thymic origin. In conclusion, LR17938 may represent a useful treatment to prevent NEC. The mechanism of protection by LR17938 involves modulation of the balance between Tem and Treg cells. These T cell subsets might be potential biomarkers and therapeutic targets during intestinal inflammation.

Sign in / Sign up

Export Citation Format

Share Document