Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers

The outcome ofMycobacterium tuberculosis(Mtb) infection ranges from a complete pathogen clearance through asymptomatic latent infection (LTBI) to active tuberculosis (TB) disease. It is now understood that LTBI and active TB represent a continuous spectrum of states with different degrees of pathogen “activity,” host pathology, and immune reactivity. Therefore, it is important to differentiate LTBI and active TB and identify active TB stages. CD4+T cells play critical role duringMtbinfection by mediating protection, contributing to inflammation, and regulating immune response. Th1 and Th17 cells are the main effector CD4+T cells during TB. Th1 cells have been shown to contribute to TB protection by secreting IFN-γand activating antimycobacterial action in macrophages. Th17 induce neutrophilic inflammation, mediate tissue damage, and thus have been implicated in TB pathology. In recent years new findings have accumulated that alter our view on the role of Th1 and Th17 cells duringMtbinfection. This review discusses these new results and how they can be implemented for TB diagnosis and monitoring.

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Abstract 3598: Critical Role of Th17-CD4 + T cells in Angiogenic Response to Hindlimb Ischemia in Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_448-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Takeki Hata ◽

Masafumi Takahashi ◽

Masanori Kawaguchi ◽

Yuichiro Kashima ◽

Yuji Shiba ◽

...

Keyword(s):

T Cells ◽

Blood Flow ◽

Th17 Cells ◽

Critical Role ◽

Interleukin 17 ◽

Hindlimb Ischemia ◽

Capillary Formation ◽

Angiogenic Response ◽

Flow Perfusion

Background: Accumulating evidence indicates that CD4 + T cells contribute to the development of collateral vesssels in ischemic tissue; however, little is known about the responsible subset of CD4 + T cells in the induction of angiogenesis. Th17 cells are recently identified as a new subset of CD4 + T cells and have been associated with the pathogenesis of certain autoimmune diseases. Th17 cells specifically secrete interleukin-17 (IL-17) and regulate various biological functions. The purpose of this study is to investigate the role of CD4 + T and Th17 cells in angiogenic response to hindlimb ischemia. Methods and Results: Unilateral hindlimb ischemia was produced in wild-type (WT: C57BL/6, 8- to 10-week-old) mice treated with or without a neutralizing antibody against CD4. Blood flow perfusion and capillary formation were assessed by using a laser Doppler perfusion imaging (LDPI) and CD31 immunostaining, respectively. Well-developed collateral vessels and capillary formation were observed in WT mice in response to hindlimb ischemia. Treatment with a neutralizing anti-CD4 antibody resulted in almost complete CD4 + T cell depletion (flow cytometry analysis, control: 45.4% vs. antibody: 1.0%) and a significant decrease in angiogenesis after the induction of hindlimb ischemia (LDPI, 21 days, control: 0.61 ± 0.1 vs. antibody: 0.41 ± 0.1, p<0.05). IL-17-deficient (IL-17 −/− ) mice also showed a significant reduction of blood flow perfusion, compared with WT mice (LDPI, day 14: 0.56 ± 0.3 vs. 0.31 ± 0.2, p<0.05; day 21: 0.66 ± 0.3 vs. 0.37 ± 0.3, p=0.05). IL-17 −/− mice had severe ischemic damage of the limb and resulted in a 25% incidence of autoamputation by day 21 (no limb loss in WT mice). Furthermore, capillary formation was also decreased significantly in IL-17 −/− mice (692.9 ± 165.6/mm 2 vs. 1223.3 ± 267.3/mm 2 , p<0.01). Conclusion : These findings demonstrate that Th17 cells, a new subset of CD4 + T cells, contribute to the angiogenic response to hindlimb ischemia and provide new insights into the mechanism by which T cells promote collateral development and angiogenesis.

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Regulation of Autoreactive CD4 T Cells by FoxO1 Signaling in CNS Autoimmunity

10.21203/rs.3.rs-322045/v1 ◽

2021 ◽

Author(s):

Emma E. Kraus ◽

Laura Kakuk-Atkins ◽

Marissa F. Farinas ◽

Mathew Jeffers ◽

Amy E. Lovett-Racke ◽

...

Keyword(s):

T Cells ◽

Transcription Factor ◽

Cd4 T Cells ◽

Th17 Cells ◽

Foxp3 Expression ◽

Treg Cells ◽

Th1 Cells ◽

T Effector Cells ◽

Cns Autoimmunity

Abstract BackgroundMyelin-specific CD4 T effector cells (Teffs), Th1 and Th17 cells, are encephalitogenic in experimental autoimmune encephalomyelitis (EAE), a well-defined murine model of multiple sclerosis (MS) and implicated in MS pathogenesis. Forkhead box O 1 (FoxO1) is a conserved effector molecule in PI3K/Akt signaling and critical in the differentiation of CD4 T cells into T helper subsets. However, it is still unclear whether FoxO1 may be a target for redirecting CD4 T cell differentiation and benefit CNS autoimmunity. MethodsUsing a selective FoxO1 inhibitor AS1842856, we determined the effects of FoxO1 inhibition in regulating myelin-specific Th1 and Th17 cells, and the transcriptional balance of T-bet and Foxp3 in myelin-specific CD4 T cells from EAE mice. The effects of AS1842856 in regulating the encephalitogenicity of myelin-specific T cells and the expansion of human Th1 cells from MS patients were also characterized. Furthermore, we characterized the potential role of FoxO1 in mediating PD-1 signaling in CD4 T cells, critical for regulating Teff and Treg cells. ResultsInhibition of FoxO1 suppressed the differentiation and expansion of Th1 cells. Moreover, the transdifferentiation of Th17 cells into encephalitogenic Th1-like cells was suppressed by FoxO1 inhibition upon reactivation of myelin-specific CD4 T cells from mice with EAE. When FoxO1 was inhibited in myelin-specific CD4 T cells, the transcriptional balance skewed from the Th1 transcription factor T-bet toward the Treg transcription factor Foxp3. Myelin-specific CD4 T cells treated with the FoxO1 inhibitor were less encephalitogenic in adoptive transfer EAE studies compared to control-treated cells. Inhibition of FoxO1 in T cells from MS patients significantly suppressed the expansion of Th1 cells. Furthermore, the immune checkpoint programmed cell death protein-1 (PD-1)-induced Foxp3 expression in CD4 T cells was impaired by FoxO1 inhibition, consistent with a bias toward Treg induction. ConclusionsThese data illustrate an important role of FoxO1 signaling in CNS autoimmunity via regulating autoreactive Teff and Treg balance.

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The critical role of T cells in glucocorticoid-induced osteoporosis

Cell Death and Disease ◽

10.1038/s41419-020-03249-4 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Lin Song ◽

Lijuan Cao ◽

Rui Liu ◽

Hui Ma ◽

Yanan Li ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Steady State ◽

Side Effects ◽

Critical Role ◽

Wild Type ◽

Receptor Activator ◽

Steady State Levels ◽

Induced Apoptosis

AbstractGlucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.

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Rapid Development of Th2 Activity During T Cell Priming

Clinical and Developmental Immunology ◽

10.1080/10446670310001598537 ◽

2003 ◽

Vol 10 (1) ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Adam F. Cunningham ◽

Kai-Michael Toellner

Keyword(s):

T Cells ◽

T Cell ◽

Rapid Development ◽

Critical Role ◽

Cell Polarization ◽

Th2 Cells ◽

Th1 Cells ◽

T Helper ◽

Th 1 ◽

Th1 And Th2

The paradigm of T helper-1 (Th-1) and Th-2 cells developing from non-committed naïve precursors is firmly established. Th1 cells are characterized by IFN production and, in mice, the selective switching to IgG2a. Conversely IL-4 production and selective switching to IgG1 and IgE characterize Th2 cells. Analysis of Th2 inductionin vitroindicates that this polarization develops gradually in T cells activated by anti-CD3 in the presence of IL-4; conversely anti-CD3 and IFN induce Th1 cells. In this report, we explore evidence that indicates that the T helper cell polarizationin vivocannot solely be explained by the cytokine environment. This is provided by studying the early acquisition of Th1 and Th2 activities during responses to a mixture of Th1 and Th2-inducing antigens. It is shown that these divergent forms of T cell help can rapidly develop in cells within a single lymph node. It is argued that early polarization to show Th-1 or Th-2 behavior can be induced by signals delivered during cognate interaction between virgin T cells and dendritic cells, in the absence of type 1 or type 2 cytokines. This contrasts with the critical role of the cytokines in reinforcing the Th-phenotype and selectively expanding T helper clones.

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IL-36R ligands are potent regulators of dendritic and T cells

Blood ◽

10.1182/blood-2011-05-356873 ◽

2011 ◽

Vol 118 (22) ◽

pp. 5813-5823 ◽

Cited By ~ 177

Author(s):

Solenne Vigne ◽

Gaby Palmer ◽

Céline Lamacchia ◽

Praxedis Martin ◽

Dominique Talabot-Ayer ◽

...

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Critical Role ◽

T Helper ◽

Innate And Adaptive Immunity ◽

Murine Bone Marrow ◽

Intracellular Signals ◽

Tnf Α ◽

Ifn Γ

Abstract IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36γ (IL-1F9) are members of the IL-1 family of cytokines. These cytokines bind to IL-36R (IL-1Rrp2) and IL-1RAcP, activating similar intracellular signals as IL-1, whereas IL-36Ra (IL-1F5) acts as an IL-36R antagonist (IL-36Ra). In this study, we show that both murine bone marrow-derived dendritic cells (BMDCs) and CD4+ T lymphocytes constitutively express IL-36R and respond to IL-36α, IL-36β, and IL-36γ. IL-36 induced the production of proinflammatory cytokines, including IL-12, IL-1β, IL-6, TNF-α, and IL-23 by BMDCs with a more potent stimulatory effect than that of other IL-1 cytokines. In addition, IL-36β enhanced the expression of CD80, CD86, and MHC class II by BMDCs. IL-36 also induced the production of IFN-γ, IL-4, and IL-17 by CD4+ T cells and cultured splenocytes. These stimulatory effects were antagonized by IL-36Ra when used in 100- to 1000-fold molar excess. The immunization of mice with IL-36β significantly and specifically promoted Th1 responses. Our data thus indicate a critical role of IL-36R ligands in the interface between innate and adaptive immunity, leading to the stimulation of T helper responses.

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PL1-2. The role of inflammasome processed cytokines in driving Th17 cells and IL-17 producing γδ T cells in infection and autoimmunity

Cytokine ◽

10.1016/j.cyto.2011.07.293 ◽

2011 ◽

Vol 56 (1) ◽

pp. 3

Author(s):

Kingston H.G. Mills ◽

Aisling Dunne ◽

Lara Dungan ◽

Jean Fletcher ◽

Sarah Higgins ◽

...

Keyword(s):

T Cells ◽

Th17 Cells ◽

Γδ T Cells

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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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The microbiota plays a critical role in the reactivity of lung immune components to innate ligands

10.1101/2020.10.19.345116 ◽

2020 ◽

Author(s):

Quentin Marquant ◽

Daphné Laubreton ◽

Carole Drajac ◽

Elliot Mathieu ◽

Edwige Bouguyon ◽

...

Keyword(s):

Immune Responses ◽

Critical Role ◽

Innate Immune ◽

Immune Reactivity ◽

Innate Immune Responses ◽

Plain Language ◽

Pulmonary Tissue ◽

Germ Free ◽

Syncytial Virus

AbstractThe microbiota contributes to shaping efficient and safe immune defenses in the gut. However, little is known about the role of the microbiota in the education of pulmonary innate immune responses. Here, we tested whether the endogenous microbiota can modulate reactivity of pulmonary tissue to pathogen stimuli by comparing the response of specific pathogen-free (SPF) and germ-free (GF) mice. Using SPF and GF mice intranasally exposed to lipopolysaccharide (LPS), a component of Gram-negative bacteria, we observed earlier and greater inflammation in the pulmonary compartment of GF mice than that of SPF mice. Toll-like receptor 4 (TLR4) was more abundantly expressed in the lungs of GF mice than those of SPF mice at steady state, which could predispose the innate immunity of GF mice to strongly react to environmental stimuli. Lung explants were stimulated with different TLR agonists or infected with the human airways pathogen, respiratory syncytial virus (RSV), resulting in greater inflammation under almost all conditions for the GF explants. Finally, alveolar macrophages (AM) from GF mice presented a higher innate immune response upon RSV infection than those of SPF mice. Overall, these data suggest that the presence of microbiota in SPF mice induced a process of innate immune tolerance in the lungs by a mechanism which remains to be elucidated. Our study represents a step forward to establishing the link between the microbiota and the immune reactivity of the lungs.Plain Language summaryMicrobiota represents an important partner of immunologic system at the interface between immune cells and epithelium. It is well known, notably in the gut, that the microbiota contributes in shaping efficient and safe defenses. However, little is known about the role of the microbiota in the education of pulmonary innate immune responses. In this study, we postulate that endogenous microbiota could dampen an excessive reactivity of pulmonary tissue to external stimuli. Thus, we sought to study the innate immune reaction switched on by viral or bacterial ligands in respiratory tract cells coming from mice with or without microbiota (germ-free condition, GF). Altogether, our results show a higher inflammatory reaction in GF condition. This study represents a step forward to better establish the link between the microbiota and the reactivity of the lung tissue. Not only these data demonstrate that the microbiota educates the pulmonary innate immune system, but also contributes the emerging concept of using respiratory commensal bacteria as potential next-generation probiotics to prevent susceptibility to respiratory diseases.

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The role of the Th1 transcription factor T-bet in a mouse model of immune-mediated bone-marrow failure

Blood ◽

10.1182/blood-2009-03-211383 ◽

2010 ◽

Vol 115 (3) ◽

pp. 541-548 ◽

Cited By ~ 22

Author(s):

Yong Tang ◽

Marie J. Desierto ◽

Jichun Chen ◽

Neal S. Young

Keyword(s):

Bone Marrow ◽

T Cells ◽

Transcription Factor ◽

Transforming Growth Factor ◽

Bone Marrow Failure ◽

Critical Role ◽

Interferon Γ ◽

Interleukin 17 ◽

Immune Mediated

Abstract The transcription factor T-bet is a key regulator of type 1 immune responses. We examined the role of T-bet in an animal model of immune-mediated bone marrow (BM) failure using mice carrying a germline T-bet gene deletion (T-bet−/−). In comparison with normal C57BL6 (B6) control mice, T-bet−/− mice had normal cellular composition in lymphohematopoietic tissues, but T-bet−/− lymphocytes were functionally defective. Infusion of 5 × 106 T-bet−/− lymph node (LN) cells into sublethally irradiated, major histocompatibility complex–mismatched CByB6F1 (F1) recipients failed to induce the severe marrow hypoplasia and fatal pancytopenia that is produced by injection of similar numbers of B6 LN cells. Increasing T-bet−/− LN-cell dose to 10 to 23 × 106 per recipient led to only mild hematopoietic deficiency. Recipients of T-bet−/− LN cells had no expansion in T cells or interferon-γ–producing T cells but showed a significant increase in Lin−Sca1+CD117+CD34− BM cells. Plasma transforming growth factor-β and interleukin-17 concentrations were increased in T-bet−/− LN-cell recipients, possibly a compensatory up-regulation of the Th17 immune response. Continuous infusion of interferon-γ resulted in hematopoietic suppression but did not cause T-bet−/− LN-cell expansion or BM destruction. Our data provided fresh evidence demonstrating a critical role of T-bet in immune-mediated BM failure.

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Abstract WMP73: Peripheral T Cells From MCAO Mice Contribute to Microglial Polarization

Stroke ◽

10.1161/str.48.suppl_1.wmp73 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Dan Ye ◽

Yun Xu

Keyword(s):

T Cells ◽

Th17 Cells ◽

Inflammatory Cells ◽

Treg Cells ◽

Experimental Stroke ◽

Dual Roles ◽

Microglial Polarization ◽

Peripheral T Cells ◽

Anti Inflammatory

Both resident microglia and infiltrated peripheral T cells have been proved to play important roles in the pathology of stroke. It is well accepted that activated microglia exert dual roles, including pro-inflammatory (M1) and anti-inflammatory (M2) functions. However, the mechanism regulating microglial polarization remains elusive. T cells are recruited into the ischemic area within 24 h after stroke, which also exhibit pro-inflammatory (Th1, Th17) and anti-inflammatory (Th2, Treg) functions. The interaction between microglia and T cells after stroke is barely understood, which may be served as modifiers of pathobiology in stroke. Here we described the role of T cells in the microglial polarization in mouse experimental stroke. We isolated T cells from spleens of MCAO mice at 24 h and 72 h, respectively, and then added to cultured microglia for 24 h. Our results indicated that splenic T cells obtained at 24 h after MCAO selectively promoted microglia polarize to a pro-inflammatory (M1) state, while T cells obtained at 72 h, favored microglia polarize to an anti-inflammatory (M2) state. The results of flow cytometry showed that Th1 and Th17 cells increased at 24 h after MCAO while Th2 and Treg cells increased at 72 h after MCAO. This study implicates that distinct subtypes of T cells contribute differentially to microglial polarization after stroke onset. Therefore, treatments aiming at modulating the ratios of T cells to anti-inflammatory cells have the potential to induce microglial polarize to M2 phenotype and improve the outcome of ischemic stroke.

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