Intestinal CD14+ Macrophages Protect CD4+ T Cells From Activation-induced Cell Death via Exosomal Membrane TNF in Crohn’s Disease

Abstract Background and aims Sustained activation of CD4+ T cells plays important roles in the pathogenesis of Crohn’s disease [CD]. Under physiologic conditions, activated T cells can be timely eliminated by a process termed activation-induced cell death [AICD], restraining T cell over-activation and preventing immunological destruction. We inquired whether defective AICD might explain CD4+ T cell over-activation in CD and investigated the underlying mechanisms. Methods CD14+ macrophages [Mφ] and CD4+ T cells were isolated from intestinal tissues or peripheral blood of controls and CD patients. An ex vivo evaluation system was employed to simulate AICD and cell apoptosis was measured by flow cytometry. Results CD4+ T cells from CD patients fail to undergo AICD in the ex vivo system. Specifically, proinflammatory type 1 helper T [Th1] and type 17 helper T [Th17] cells, rather than immunosuppressive regulatory T [Treg] cells evade AICD in CD. CD14+ Mφ in the intestinal inflammatory microenvironment of CD promote AICD resistance in CD4+ T cells via a cell-to-cell contact-independent manner. Mechanistically, CD14+ Mφ released exosomes express membrane tumour necrosis factor [TNF] which engages TNFR2 on CD4+ T cells and triggers NF-κB signalling, thereby causing AICD resistance. Importantly, clinically applicable anti-TNF antibodies effectively blocked exosomal membrane TNF-induced CD4+ T cell AICD resistance. Conclusions CD14+ Mφ participate in CD pathogenesis by inducing AICD resistance through release of exosomal membrane TNF to activate the TNFR2/NF-κB pathway in CD4+ T cells. These results present new insights into CD pathogenesis and extend mechanistic understanding of anti-TNF agents. Proposed model CD14+ Mφ in the intestinal microenvironment of CD patients maintain the sustained activation of CD4+ T cells through exosomal membrane TNF to induce apoptosis resistance via TNFR2/NF-κB signalling, which could be effectively blocked by clinically applicable anti-TNF agents.

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W1811 The Significance of Monitoring Peripheral CD4+ T-Cells Expressing Regulatory CD25High+ Phenotype and the Immuno-Deficiency CD4+ T-Cell Phenotype Lacking CD28 in Patients With Crohn's Disease Under Infliximab Therapy

Gastroenterology ◽

10.1016/s0016-5085(10)63431-2 ◽

2010 ◽

Vol 138 (5) ◽

pp. S-745

Author(s):

Koji Kamikozuru ◽

Ken Fukunaga ◽

Yoko Yokoyama ◽

Hiroto Miwa ◽

Takayuki Matsumoto

Keyword(s):

T Cells ◽

Crohn’S Disease ◽

T Cell ◽

Crohn's Disease ◽

Cd4 T Cells ◽

Infliximab Therapy ◽

Cd4 T Cell ◽

Cell Phenotype

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CD4+ Tissue-resident Memory T Cells Expand and Are a Major Source of Mucosal Tumour Necrosis Factor α in Active Crohn’s Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz010 ◽

2019 ◽

Vol 13 (7) ◽

pp. 905-915 ◽

Cited By ~ 9

Author(s):

Shrinivas Bishu ◽

Mohammed El Zaatari ◽

Atsushi Hayashi ◽

Guoqing Hou ◽

Nicole Bowers ◽

...

Keyword(s):

T Cells ◽

Crohn’S Disease ◽

T Cell ◽

Crohn's Disease ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Ex Vivo ◽

Factor Α ◽

And Control ◽

Necrosis Factor

Abstract Background and Aims Tumour necrosis factor [TNF]α- and IL-17A-producing T cells are implicated in Crohn’s disease [CD]. Tissue-resident memory T [TRM] cells are tissue-restricted T cells that are regulated by PR zinc finger domain 1 [PRDM1], which has been implicated in pathogenic Th17 cell responses. TRM cells provide host defence but their role in CD is unknown. We thus examined CD4+ TRM cells in CD. Methods Colon samples were prospectively collected at endoscopy or surgery in CD and control subjects. Flow cytometry and ex vivo assays were performed to characterise CD4+ TRM cells. Results CD4+ TRM cells are the most abundant memory T cell population and are the major T cell source of mucosal TNFα in CD. CD4+ TRM cells are expanded in CD and more avidly produce IL-17A and TNFα relative to control cells. There was a unique population of TNFα+IL-17A+ CD4+ TRM cells in CD which are largely absent in controls. PRDM1 was highly expressed by CD4+ TRM cells but not by other effector T cells. Suppression of PRDM1 was associated with impaired induction of IL17A and TNFA by CD4+ TRM cells Conclusions CD4+ TRM cells are expanded in CD and are a major source of TNFα, suggesting that they are important in CD. PRDM1 is expressed by TRM cells and may regulate their function. Collectively, this argues for prospective studies tracking CD4+ TRM cells over the disease course.

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Loss of EBV-Specific CD4+T Cells during Progression to EBV-Related AIDS Non-Hodgkin Lymphoma: Restoration by Highly Active Antiretroviral Therapy (HAART).

Blood ◽

10.1182/blood.v104.11.3110.3110 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3110-3110

Author(s):

Erwan R. Piriou ◽

Christine Jansen ◽

Karel van Dort ◽

Iris De Cuyper ◽

Nening M. Nanlohy ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Cd4 T Cells ◽

Antigen Processing ◽

Ex Vivo ◽

T Cell Response ◽

Cd4 T Cell ◽

Cell Numbers

Abstract Objective: EBV-specific CD8+ T cells have been extensively studied in various settings, and appear to play a major role in the control of EBV-related malignancies. In contrast, it is still unclear whether EBV-specific CD4+ T cells play a role in vivo. To study this question, an assay was developed to measure the CD4+ T-cell response towards two EBV antigens, in both healthy (n=14) and HIV-infected subjects (n=23). In addition, both HAART-treated (n=12) and untreated HIV+ individuals (n=14) - including progressors to EBV-related lymphoma - were studied longitudinally. Methods: EBV-specific CD4+ T cells were stimulated with peptide pools from latent protein EBNA1 and lytic protein BZLF1, and detected by measurement of IFNg-production. Results: After direct ex vivo stimulation, EBNA1 or BZLF1-specific IFNg- (and/or IL2) producing CD4+ T cell numbers were low, and measurable in less than half of the subjects studied (either HIV- and HIV+). Therefore, PBMC were cultured for 12 days in the presence of peptides and IL2 (from day 3), and then restimulated with peptides, allowing specific and reproducible expansion of EBV-specific CD4+ T cells, independent of HLA type and ex vivo antigen processing. Interestingly, numbers of EBV-specific CD4+ T cells inversely correlated with EBV viral load, implying an important role for EBV-specific CD4+ T cells in the control of EBV in vivo. Untreated HIV-infected individuals had a lower CD4+ T cell response to EBNA1 and BZLF1 as compared to healthy EBV carriers and HAART-treated HIV+ subjects. In longitudinal samples, EBNA1-specific, but not BZLF1-specific T-cell numbers increased after HAART, while EBV load was not affected by treatment. In all the progressors to EBV-related lymphoma, EBV-specific CD4+ T cells were lost at least 24 months before lymphoma diagnosis. Conclusions: Both cross-sectional and longitudinal data suggest an important role for EBV-specific CD4+ T cells in the control of EBV-related malignancies. Furthermore, it seems that HAART treatment leads to recovery of EBNA1-specific, but not BZLF1-specific CD4+ T-cell responses, implying changes in the latency pattern of EBV, despite an unaltered cell-associated EBV DNA load. Thus, early HAART treatment might prevent loss of specific CD4+ T-cell help and progression to NHL.

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Deciphering the Plasmodium falciparum malaria-specific CD4+ T cell response: ex vivo detection of high frequencies of PD-1+TIGIT+ EXP1-specific CD4+ T cells using a novel HLA-DR11-restricted MHC class II tetramer

Clinical & Experimental Immunology ◽

10.1093/cei/uxab027 ◽

2021 ◽

Author(s):

Sophia Schulte ◽

Janna Heide ◽

Christin Ackermann ◽

Sven Peine ◽

Michael Ramharter ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

Cell Response ◽

Cd4 T Cells ◽

Ex Vivo ◽

Class Ii ◽

T Cell Response ◽

Cd4 T Cell ◽

Inhibitory Receptors

Abstract Relatively little is known about the ex vivo frequency and phenotype of the P. falciparum-specific CD4+ T cell response in humans. The exported protein 1 (EXP1) is expressed by plasmodia at both, the liver stage and blood stage, of infection making it a potential target for CD4+ and CD8+ effector T cells. Here, a fluorochrome-labelled HLA-DRB1*11:01-restriced MHC class II tetramer derived from the P. falciparum EXP1 (aa62-74) was established for ex vivo tetramer analysis and magnetic bead enrichment in ten patients with acute malaria. EXP1-specific CD4+ T cells were detectable in nine out of ten (90%) malaria patients expressing the HLA-DRB1*11 molecule with an average ex vivo frequency of 0.11% (0-0.22%) of total CD4+ T cells. The phenotype of EXP1-specific CD4+ T cells was further assessed using co-staining with activation (CD38, HLA-DR, CD26), differentiation (CD45RO, CCR7, KLRG1, CD127), senescence (CD57) and co-inhibitory (PD-1, TIGIT, LAG-3, TIM-3) markers as well as the ectonucleotidases CD39 and CD73. EXP1-specific tetramer+ CD4+ T cells had a distinct phenotype compared to bulk CD4+ T cells and displayed a highly activated effector memory phenotype with elevated levels of co-inhibitory receptors and activation markers: EXP1-specific CD4+ T cells universally expressed the co-inhibitory receptors PD-1 and TIGIT as well as the activation marker CD38 and showed elevated frequencies of CD39. These results demonstrate that MHC class II tetramer enrichment is a sensitive approach to investigate ex vivo antigen-specific CD4+ T cells in malaria patients that will aid further analysis of the role of CD4+ T cells during malaria.

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Idiopathic CD4 T Cell Lymphocytopenia: A Case of Overexpression of PD-1/PDL-1 and CTLA-4

Infectious Disease Reports ◽

10.3390/idr13010009 ◽

2021 ◽

Vol 13 (1) ◽

pp. 72-81

Author(s):

Gaurav Kumar ◽

Heidy Schmid-Antomarchi ◽

Annie Schmid-Alliana ◽

Michel Ticchioni ◽

Pierre-Marie Roger

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Ex Vivo ◽

Cd4 T Cell ◽

Apoptotic Pathway ◽

Cell Functions ◽

Inhibitory Molecules ◽

Cd4 T Cell Count ◽

Costimulatory Pathway

Idiopathic CD4 T cell lymphocytopenia (ICL) is a rare entity characterized by CD4 T cell count of <300 cells/mm3 along with opportunistic infection for which T cell marker expression remains to be fully explored. We report an ICL case for which T lymphocyte phenotype and its costimulatory molecules expression was analyzed both ex vivo and after overnight stimulation through CD3/CD28. The ICL patient was compared to five healthy controls. We observed higher expression of inhibitory molecules PD-1/PDL-1 and CTLA-4 on CD4 T cells and increased regulatory T cells in ICL, along with high activation and low proliferation of CD4 T cells. The alteration in the expression of both the costimulatory pathway and the apoptotic pathway might participate to down-regulate both CD4 T cell functions and numbers observed in ICL.

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IL-12 and Mucosal CD14+ Monocyte-Like Cells Induce IL-8 in Colonic Memory CD4+ T Cells of Patients With Ulcerative Colitis but not Crohn’s Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz115 ◽

2019 ◽

Vol 14 (1) ◽

pp. 79-95 ◽

Cited By ~ 4

Author(s):

Laurence Chapuy ◽

Marwa Bsat ◽

Manuel Rubio ◽

Sisi Sarkizova ◽

Amélie Therrien ◽

...

Keyword(s):

Ulcerative Colitis ◽

T Cells ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Cd4 T Cells ◽

Ex Vivo ◽

Mononuclear Phagocytes ◽

Phenotypic Analysis ◽

Gm Csf ◽

Ifn Γ

Abstract Background and Aims CD14+ mononuclear phagocytes [MNPs] and T cells infiltrate colon in ulcerative colitis [UC]. Here we investigated how CD14+ MNPs and the cytokines they produce shape the colonic effector T cell profile. Methods Colonic or mesenteric lymph node [mLNs] CD4+ T cells isolated from UC or Crohn’s disease [CD] patients were stimulated with cytokines or autologous CD14+ MNPs. Cytokine expression was assessed by intracytoplasmic staining and multiplex ELISA. Unsupervised phenotypic multicolour analysis of colonic CD14+ MNPs was performed using the FlowSOM algorithm. Results Among CD14+CD64+HLA-DR+SIRPα + MNPs, only the pro-inflammatory cytokine-producing CD163− subpopulation accumulated in inflamed UC colon and promoted mucosal IL-1β-dependent Th17, Th17/Th1, Th17/Th22 but not Th1 responses. Unsupervised phenotypic analysis of CD14+CD64+ MNPs segregated CD163− monocyte-like cells and CD163+ macrophages. Unexpectedly, IL-12, IL-1β and CD163−, but not CD163+, cells induced IL-8 expression in colonic CD4+ T cells, which co-expressed IFN-γ and/or IL-17 in UC and not CD. The CD163− monocyte-like cells increased the frequency of IL-8+IL-17+/−IFN-γ +/− T cells through IL-1β and IL-12. Finally, colonic IL-8+ T cells co-expressing GM-CSF, TNF-α and IL-6 were detected ex vivo and, promoted by IL-12 in the mucosa and mLNs in UC only. Conclusions Our findings established a link between monocyte-like CD163− MNPs, IL-12, IL-1β and the detection of colonic memory IL-8-producing CD4+ T cells, which might all contribute to the pathogenesis of UC.

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Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals.

Journal of Experimental Medicine ◽

10.1084/jem.175.2.331 ◽

1992 ◽

Vol 175 (2) ◽

pp. 331-340 ◽

Cited By ~ 605

Author(s):

H Groux ◽

G Torpier ◽

D Monté ◽

Y Mouton ◽

A Capron ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Cell Death ◽

T Cell ◽

Cell Population ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Death Process ◽

Immunodeficiency Virus ◽

Asymptomatic Individuals

In immature thymocytes, T cell receptor for antigen (TCR) mobilization leads to an active T cell suicide process, apoptosis, which is involved in the selection of the T cell repertoire. We have proposed that inappropriate induction of such a cell death program in the mature CD4+ T cell population could account for both early qualitative and late quantitative CD4+ T lymphocyte defects of human immunodeficiency virus (HIV)-infected individuals (Ameisen, J.C., and A. Capron. 1991. Immunol. Today. 4:102). Here, we report that the selective failure of CD4+ T cells from 59 clinically asymptomatic HIV-infected individuals to proliferate in vitro to TCR mobilization by major histocompatibility complex class II-dependent superantigens and to pokeweed mitogen (PWM) is due to an active CD4+ T cell death process, with the biochemical and ultrastructural features of apoptosis. Activation-induced cell death occurred only in the CD4+ T cell population from HIV-infected asymptomatic individuals and was not observed in T cells from any of 58 HIV-seronegative controls, including nine patients with other acute or chronic infectious diseases. Activation-induced CD4+ T cell death was prevented by cycloheximide, cyclosporin A, and a CD28 monoclonal antibody (mAb). The CD28 mAb not only prevented apoptosis but also restored T cell proliferation to stimuli, including PWM, superantigens, and the tetanus and influenza recall antigens. These findings may have implications for the understanding of the pathogenesis of acquired immune deficiency syndrome and for the design of specific therapeutic strategies.

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A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

Cell Death and Differentiation ◽

10.1038/sj.cdd.4401441 ◽

2004 ◽

Vol 11 (9) ◽

pp. 1017-1027 ◽

Cited By ~ 15

Author(s):

J D Lelièvre ◽

F Mammano ◽

D Arnoult ◽

F Petit ◽

A Grodet ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Dying Cells

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Restriction of HIV-1 replication in macrophages and CD4+ T cells from HIV controllers

Blood ◽

10.1182/blood-2010-12-327106 ◽

2011 ◽

Vol 118 (4) ◽

pp. 955-964 ◽

Cited By ~ 87

Author(s):

Asier Sáez-Cirión ◽

Chiraz Hamimi ◽

Anna Bergamaschi ◽

Annie David ◽

Pierre Versmisse ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Ex Vivo ◽

Cd4 T Cell ◽

Viral Reservoir ◽

Cell Resistance ◽

Viral Control ◽

Hiv Controllers ◽

Hiv 1

Abstract How HIV controllers (HICs) maintain undetectable viremia without therapy is unknown. The strong CD8+ T-cell HIV suppressive capacity found in many, but not all, HICs may contribute to long-lasting viral control. However, other earlier defense mechanisms may be involved. Here, we examined intrinsic HIC cell resistance to HIV-1 infection. After in vitro challenge, monocyte-derived macrophages and anti–CD3-activated CD4+ T cells from HICs showed low HIV-1 susceptibility. CD4 T-cell resistance was independent of HIV-1 coreceptors and affected also SIVmac infection. CD4+ T cells from HICs expressed ex vivo higher levels of p21Waf1/Cip1, which has been involved in the control of HIV-1 replication, than cells from control subjects. However, HIV restriction in anti–CD3-activated CD4+ T cells and macrophages was not associated with p21 expression. Restriction inhibited accumulation of reverse transcripts, leading to reduction of HIV-1 integrated proviruses. The block could be overcome by high viral inocula, suggesting the action of a saturable mechanism. Importantly, cell-associated HIV-1 DNA load was extremely low in HICs and correlated with CD4+ T-cell permissiveness to infection. These results point to a contribution of intrinsic cell resistance to the control of infection and the containment of viral reservoir in HICs.

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