scholarly journals Functional abnormalities of CD8+ T cells define a unique subset of patients with common variable immunodeficiency

Blood ◽  
1993 ◽  
Vol 82 (1) ◽  
pp. 192-201 ◽  
Author(s):  
JS Jaffe ◽  
W Strober ◽  
MC Sneller
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cd8 T Cells ◽  
Common Variable Immunodeficiency ◽  
Cytokine Production ◽  
Interleukin 2 ◽  
T Cell Subsets ◽  
Cell Phenotype ◽  
Common Variable

A substantial subgroup of patients with common variable immunodeficiency (CVI) exhibit an abnormal T-cell phenotype characterized by a low CD4/CD8 ratio associated with a significant increase in the absolute number of CD8+ T cells (CVI4/8low patients). In the present study, we examined the phenotypic and functional properties of purified T-cell subsets in this group of CVI patients. CD8+ T cells from CVI4/8low patients manifested increased expression of HLA-DR and CD57 and decreased expression of CD45RA as compared with CD8+ T cells from normal controls. When stimulated with anti-CD3 and phorbol 12-myristate 13-acetate, purified patient CD8+ T cells exhibited significantly decreased proliferation, c-myc expression, and interleukin-2 (IL-2) production compared with that of normal CD8+ T cells. Nevertheless, mitogen-activated patient CD8+ T cells secreted elevated amounts of gamma-interferon and IL-5 and normal amounts of IL- 4. This abnormal pattern of proliferation and cytokine production was limited to the CD8+ T-cell subset as CD4+ T cells from these patients exhibited normal proliferation and cytokine production. In further functional studies, purified CD8+ T cells from CVI4/8low patients manifested increased cytotoxic T-lymphocyte activity and suppressor activity, as compared with normal CD8+ T cells, when they were tested in (1) an anti-CD3 “redirected” cytotoxicity assay and (2) a suppressor assay consisting of CD8+ T cells and Staphylococcus aureus Cowan I (SAC) plus IL-2-stimulated normal (allogeneic) B cells. In the latter case, patient CD8+ T cells suppressed IgG production, but not IgM production. Finally, in studies to evaluate the role of patient CD8+ T cells in the pathogenesis of hypogammaglobulinemia, we determined the capacity of SAC and IL-2 to induce Ig production in highly purified patient B cells, ie, in the absence of patient CD8+ T cells. We found that, whereas B cells from one patient produced normal amounts of IgG, B cells from three patients were unable to produce normal amounts of IgG under these conditions. These data establish the phenotypic and functional characteristics of CD8+ T cells in CVI4/8low and clearly distinguish CVI4/8low patients from other patients with this syndrome. The data do not support the contention that hypogammaglobulinemia in CVI4/8low patients is due to a direct effect of CD8+ T cells on terminal B-cell differentiation, except in the occasional patient. The abnormal CD8+ T cells may, nevertheless, have more subtle effects of lymphoid function that play a role in disease pathogenesis.

scholarly journals Characterization of common variable immunodeficiency: identification of a subset of patients with distinctive immunophenotypic and clinical features [see comments]

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 2046-2051 ◽  
Author(s):  
JJ Wright ◽  
DK Wagner ◽  
RM Blaese ◽  
C Hagengruber ◽  
TA Waldmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Features ◽  
Cd8 T Cells ◽  
Common Variable Immunodeficiency ◽  
Interleukin 2 ◽  
Delayed Type Hypersensitivity ◽  
Activation Markers ◽  
Common Variable

The peripheral blood lymphocyte surface markers and clinical features of 38 patients with common variable immunodeficiency (CVID) were assessed. These studies identified a subset of CVID consisting of 14 of the 38 patients with a distinctive T-cell immunophenotype and clinical findings. The phenotypic changes were characterized by an abnormally low CD4/CD8 ratio (less than or equal to 0.9) due primarily to a significant increase in CD8 T cells. In addition, there was an expansion in CD8 T cells coexpressing CD57 and increased expression of the activation markers HLA-DR and interleukin-2 receptor (IL-2R) by these cells. This group of immunophenotypically abnormal CVID patients also had characteristic clinical features, including splenomegaly (P less than .02) and in vivo T-cell dysfunction based on the evaluation of delayed-type hypersensitivity (P less than .05). Approximately 71% of these patients had splenomegaly and 42% were anergic in contrast to the remaining group of CVID patients, in which 29% had splenomegaly and 7% were anergic. These findings define a subgroup of CVID patients that have specific immunophenotypic features and functional T-cell abnormalities.

scholarly journals Characterization of common variable immunodeficiency: identification of a subset of patients with distinctive immunophenotypic and clinical features [see comments]

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 2046-2051 ◽  
Author(s):  
JJ Wright ◽  
DK Wagner ◽  
RM Blaese ◽  
C Hagengruber ◽  
TA Waldmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Features ◽  
Cd8 T Cells ◽  
Common Variable Immunodeficiency ◽  
Interleukin 2 ◽  
Delayed Type Hypersensitivity ◽  
Activation Markers ◽  
Common Variable

Abstract The peripheral blood lymphocyte surface markers and clinical features of 38 patients with common variable immunodeficiency (CVID) were assessed. These studies identified a subset of CVID consisting of 14 of the 38 patients with a distinctive T-cell immunophenotype and clinical findings. The phenotypic changes were characterized by an abnormally low CD4/CD8 ratio (less than or equal to 0.9) due primarily to a significant increase in CD8 T cells. In addition, there was an expansion in CD8 T cells coexpressing CD57 and increased expression of the activation markers HLA-DR and interleukin-2 receptor (IL-2R) by these cells. This group of immunophenotypically abnormal CVID patients also had characteristic clinical features, including splenomegaly (P less than .02) and in vivo T-cell dysfunction based on the evaluation of delayed-type hypersensitivity (P less than .05). Approximately 71% of these patients had splenomegaly and 42% were anergic in contrast to the remaining group of CVID patients, in which 29% had splenomegaly and 7% were anergic. These findings define a subgroup of CVID patients that have specific immunophenotypic features and functional T-cell abnormalities.

PD-1 Expression Defines Two Distinct T-Cell Subpopulations That Differentially Impact Patient Outcomes In Follicular Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 366-366
Author(s):  
Zhi-Zhang Yang ◽  
Deanna M. Grote ◽  
Steven C. Ziesmer ◽  
Stephen M Ansell
Keyword(s):  
Patient Outcome ◽  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
Patient Outcomes ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
T Cell Subsets ◽  
Cell Phenotype ◽  
Tfh Cells

Abstract Background The role of intratumoral PD-1+ T cells and their contribution to patient outcome in follicular lymphoma (FL) has been controversial. While some studies have found that increased numbers of PD-1+ T cells correlate with an inferior prognosis or have no impact on patient outcomes, other studies observed that the numbers of intratumoral PD-1+ T cells are an indicator of a favorable outcome in FL. In previous work, we observed that PD-1 can be expressed by different subsets of intratumoral T cells in FL including T follicular helper (TFH) cells and exhausted T effector cells. However, the function, prevalence, distribution and clinical importance of the respective intratumoral PD-1+ T subsets in FL patients are largely unknown. Goal To characterize PD-1+ T cell subsets and to determine the biological and clinical relevance of these T cell subsets in FL. Results In an analysis of biopsy specimens from 33 previously untreated FL patients, we found that PD-1 is abundantly expressed on intratumoral T cells. A median of 54.9% (range: 17.2-92.6, n=33) of CD4+ or 45.8% (range: 12.8-81.7, n=33) of CD8+ T cells express PD-1 on the cell surface. We found by flow cytometry that PD-1 is expressed on intratumoral CD4+ T cells with bright or dim intensity that represents two different subpopulations in FL. By immunohistochemistry, we identified that CD4+PD-1bright T cells predominantly reside in the lymph node follicles while PD-1dim T cells are mainly located in an inter-follicular pattern. Intratumoral CD4+PD-1bright T cells have a TFH cell phenotype and express CXCR5, secret IL-21 and are BCL-6 positive with no TIM-3 expression. In contrast, CD4+PD-1dim T cells have an exhausted phenotype, express TIM-3 and do not express BCL-6 and CXCR5. Functionally, CD4+PD-1dim T cells displayed reduced proliferation, cytokine production and cell signal transduction. When the CD8+ T cells were analyzed, we found that intratumoral CD8+ T cells, primarily reside in the inter-follicular regions, express PD-1 with low intensity and exhibit similar phenotypic and functional changes to inter-follicular CD4+PD-1dim T cells. These cells express TIM-3 but lack CXCR5 and BCL-6. They also displayed reduced proliferation and cytokine production. Clinically, we observed that both the numbers of CD4+PD-1dim and CD8+PD-1dim exhausted T cells significantly correlate with a reduced progression-free survival in FL patients treated with single agent rituximab (p=0.007 and p=0.04 respectively; n=31). Although it did not reach statistical significance, CD4+PD-1bright TFH cells appeared to correlate with a favorable survival, suggesting that TFH and exhausted T cells differentially impact patient outcome in FL. Conclusion Taken together, these results indicated that PD-1 expression defines two subpopulations with distinct functions that differentially impact patient outcome in FL. This finding provides not only an explanation for the previously discrepant clinical observations, but is also important in the design of future anti-PD-1 antibody-based therapy in FL. Disclosures: No relevant conflicts of interest to declare.

CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 195-202 ◽  
Author(s):  
Masaki Tateyama ◽  
Naoki Oyaizu ◽  
Thomas W. McCloskey ◽  
Soe Than ◽  
Savita Pahwa
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Cross Linking ◽  
Induced Apoptosis ◽  
Hiv 1

CD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis was observed in CD8+ T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell–cell contact with FasL+ CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4+ T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.

scholarly journals Ecto-5′-Nucleotidase (CD73) Regulates the Survival of CD8+ T Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Mariana V. Rosemblatt ◽  
Brian Parra-Tello ◽  
Pedro Briceño ◽  
Elizabeth Rivas-Yáñez ◽  
Suat Tucer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Cd8 T Cell ◽  
Antigenic Stimulation ◽  
T Cell Subsets ◽  
Limited Information ◽  
Α Chain ◽  
The Impact

Ecto-5′-nucleotidase (CD73) is an enzyme present on the surface of tumor cells whose primary described function is the production of extracellular adenosine. Due to the immunosuppressive properties of adenosine, CD73 is being investigated as a target for new antitumor therapies. We and others have described that CD73 is present at the surface of different CD8+ T cell subsets. Nonetheless, there is limited information as to whether CD73 affects CD8+ T cell proliferation and survival. In this study, we assessed the impact of CD73 deficiency on CD8+ T cells by analyzing their proliferation and survival in antigenic and homeostatic conditions. Results obtained from adoptive transfer experiments demonstrate a paradoxical role of CD73. On one side, it favors the expression of interleukin-7 receptor α chain on CD8+ T cells and their homeostatic survival; on the other side, it reduces the survival of activated CD8+ T cells under antigenic stimulation. Also, upon in vitro antigenic stimulation, CD73 decreases the expression of interleukin-2 receptor α chain and the anti-apoptotic molecule Bcl-2, findings that may explain the reduced CD8+ T cell survival observed in this condition. These results indicate that CD73 has a dual effect on CD8+ T cells depending on whether they are subject to an antigenic or homeostatic stimulus, and thus, special attention should be given to these aspects when considering CD73 blockade in the design of novel antitumor therapies.

scholarly journals Cytokine Production by Vγ+-T-Cell Subsets Is an Important Factor Determining CD4+-Th-Cell Phenotype and Susceptibility of BALB/c Mice to Coxsackievirus B3-Induced Myocarditis

2001 ◽  
Vol 75 (13) ◽  
pp. 5860-5869 ◽  
Author(s):  
Sally A. Huber ◽  
Danielle Graveline ◽  
Willi K. Born ◽  
Rebecca L. O'Brien
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Cytokine Production ◽  
Coxsackievirus B3 ◽  
T Cell Subsets ◽  
Single Amino Acid ◽  
Cell Phenotype ◽  
Th Cell ◽  
Ifn Γ

ABSTRACT Two coxsackievirus B3 (CVB3) variants (H3 and H310A1) differ by a single amino acid mutation in the VP2 capsid protein. H3 induces severe myocarditis in BALB/c mice, but H310A1 is amyocarditic. Infection with H3, but not H310A1, preferentially activates Vγ4 Vδ4 cells, which are strongly positive for gamma interferon (IFN-γ), whereas Vγ1 Vδ4 cells are increased in both H3 and H310A1 virus-infected animals. Depletion of Vγ1+ cells using monoclonal anti-Vγ1 antibody enhanced myocarditis and CD4+-, IFN-γ+-cell responses in both H3- and H310A1-infected mice yet decreased the CD4+-, IL-4+-cell response. Depleting Vγ4+ cells suppressed myocarditis and reduced CD4+IFN-γ+ cells but increased CD4+IL-4+ T cells. The role of cytokine production by Vγ1+ and Vγ4+ T cells was investigated by adoptively transferring these cells isolated from H3-infected BALB/c Stat4 knockout (Stat4ko) (defective in IFN-γ expression) or BALB/c Stat6ko (defective in IL-4 expression) mice into H3 virus-infected wild-type BALB/c recipients. Vγ4 and Vγ1+ T cells from Stat4ko mice expressed IL-4 but no or minimal IFN-γ, whereas these cell populations derived from Stat6ko mice expressed IFN-γ but no IL-4. Stat4ko Vγ1+ cells (IL-4+) suppress myocarditis. Stat6ko Vγ1+ cells (IFN-γ+) were not inhibitory. Stat6ko Vγ4+ cells (IFN-γ+) significantly enhanced myocarditis. Stat4ko Vγ4+ cells (IL-4+) neither inhibited nor enhanced disease. These results show that distinct γδ-T-cell subsets control myocarditis susceptibility and bias the CD4+-Th-cell response. The cytokines produced by the Vγ subpopulation have a significant influence on the CD4+-Th-cell phenotype.

scholarly journals The Immune Micro-Environment in Diffuse Large B Cell Lymphoma Is Characterised By an Immunosuppressive Shift in T Cell Subsets

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5240-5240
Author(s):  
Edward Truelove ◽  
Frances Seymour ◽  
Joseph G Taylor ◽  
Mariarita Calaminici ◽  
Andrew James Clear ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Research Funding ◽  
Cytokine Production ◽  
B Cell Lymphoma ◽  
T Cell Subsets ◽  
Large B Cell Lymphoma ◽  
Car T

Diffuse large B-cell Lymphoma (DLBCL) is the most frequent non-Hodgkin's lymphoma with 3 molecularly distinct subtypes based on cell of origin. Genetic alterations in DLBCL, expression of checkpoint molecules and an immunosuppressive microenvironment (ME) all contribute to escape from host anti-lymphoma immunity. The clinical success of monoclonal antibodies that engage the immune system and CAR-T cellular therapy have further highlighted the importance and therapeutic potential of the immune ME in DLBCL. Here we present data from comprehensive phenotyping of cell suspensions from diagnostic DLBCL and reactive lymph node / tonsil (RLNT) biopsies by cytometry by time of flight (CyTOF), with a focus on the T-cell compartment. Cryopreserved samples from 6 DLBCL (5 LN, 1 spleen) at diagnosis and 5 RLNT (3 LN, 2 tonsil) were stained with a panel of metal-tagged antibodies and analysed by CyTOF2. Samples were acquired in 2 batches with the same RLNT (LN) sample with each to ensure staining consistency. Data were normalised, uploaded to Cytobank, gated to CD45+ CD3+ live single cells and exported for further analysis with Cytofkit in R. CD3+ events were gated further into CD4+ and CD8+ subsets, which demonstrated that CD4+ T cells were the predominant phenotype in all samples. However, there was a marked skewing of the CD4:CD8 ratio, with CD4+ T cells lower as a percentage of CD3+ T cells in the DLBCL samples (55.84 v 78.18, p=0.0173*). CD8+ T cells were higher as a percentage in DLBCL (36.22 v 16.75, p=0.03*) with no difference seen in double negative (DN) T cells. CD3+ T cells were then clustered with FlowSOM and visualised according to the tSNE algorithm. A heatmap of median marker expression intensity was generated to facilitate cluster identification. This revealed a number of differences in cluster abundance between the groups, with a significant shift in differentiation away from naïve and towards an effector memory (EM) phenotype in DLBCL. There were fewer cells in the CD27+ CD28+ CCR7+ CD45RA+ CD4+ naïve cluster in the DLBCL samples than the RLNT (p=0.0173*). Although the DLBCL samples showed an overall reduction in CD4+ T cells, the clusters of regulatory T cells (Treg: CD4+ CD25+ FOXP3+ and CD127-/low) consisted of more cells from these cases than the RLNT (p=0.0043**). Within the Treg population, the DLBCL patients had more Th1 polarised (T-bet+) Tregs and more PD-1 expressing Tregs. The Th1 Tregs predominantly secreted the suppressive cytokines IL-2, IL-10 and TGF-β on stimulation and may play a role in inhibiting Th1 responses. Conventional Th1 were not increased in DLBCL resulting in a higher Th1 Treg to Th1 ratio than in RLNT. There was a trend for RLNT samples to contribute more cells to the PD-1 high follicular helper T cell (TFH) cluster and DLBCL to the PD-1+ TIM-3+ DN cluster. The DLBCL ME had relatively more CD8+ T cells and contributed more to the CCR7- CD45RA- CD8+ EM clusters (p=0.0173*) but the CD8+ T cells in the RNLT samples tended to a naïve CCR7+ CD45RA+ PD-1- phenotype (p=0.0519). The CD8+ EM cells enriched in the DLBCL ME expressed the cytotoxic markers granzyme and perforin and responded to stimulation with degranulation (CD107a) and cytokine production (IFNγ, TNFα, TGFβ and IL-10), not suggestive of exhaustion. It is also notable that a cluster of PD-1+ TIM-3+ CD8+ EM with reduced markers of cytotoxicity, low CD107a expression and poor cytokine production after stimulation was predominantly made up of cells from DLBCL suspensions (p=0.002**). CyTOF analysis of the DLBCL ME has demonstrated a shift in the balance of T cell subsets and CD4:CD8 ratio with a relative abundance of immunosuppressive Tregs despite an overall reduction in the CD4+ population and a skew towards differentiation in CD4+ and CD8+ populations. The cytotoxic T cells in DLBCL tended to have an EM phenotype and express immune checkpoint molecules but remained capable of cytokine production. However, the production of IFNγ by these effector T cells may play a role in the development of inhibitory Tregs with a Th1 phenotype, which were enriched in these patients. A cluster of CD8+ EM cells expressing checkpoint molecules and displaying characteristics of exhaustion following stimulation was also seen in these DLBCL patients. These data provide new insights into the immunosuppressive nature of the DLBCL ME and provide a rationale for targeting the ME alongside existing therapeutic approaches, including CAR-T cells to improve outcomes. Disclosures Gribben: Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 195-202 ◽  
Author(s):  
Masaki Tateyama ◽  
Naoki Oyaizu ◽  
Thomas W. McCloskey ◽  
Soe Than ◽  
Savita Pahwa
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Cross Linking ◽  
Induced Apoptosis ◽  
Hiv 1

Abstract CD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis was observed in CD8+ T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell–cell contact with FasL+ CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4+ T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.

Vitamin D Inhibits Pro-Inflammatory T Cell Function in Patients With Inflammatory Bowel Disease

2019 ◽  
Vol 13 (12) ◽  
pp. 1546-1557 ◽  
Author(s):  
Josefine Schardey ◽  
Anna-Maria Globig ◽  
Christine Janssen ◽  
Maike Hofmann ◽  
Philipp Manegold ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Vitamin D ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Bowel Disease ◽  
T Cell Subsets ◽  
Cell Phenotype ◽  
Inflammatory Bowel

Abstract Background and Aims Dysregulated T cell responses contribute to the pathogenesis of inflammatory bowel disease [IBD]. Because vitamin D [vitD] deficiency is a risk factor for adverse disease outcomes, we aimed to characterize the impact of vitD on intestinal and peripheral T cell profiles. Methods T cells were isolated from peripheral blood and intestinal biopsies of IBD patients, incubated with vitD and characterized by flow cytometry. To translate these in vitro findings to the clinic, serum vitD concentrations and clinical outcomes were correlated with T cell phenotype and function in a prospective patient cohort. Results Incubation of peripheral and intestinal T cells with 1,25(OH)2-vitD resulted in strongly reduced frequencies of pro-inflammatory CD4+ and CD8+ T cells producing interferon γ [IFNγ], interleukin-17 [IL-17], IL-22, IL-9 and tumour necrosis factor [TNF]. Univariable analysis of 200 IBD patients revealed associations of vitD deficiency with non-compliant vitD intake, season of the year and anaemia in Crohn’s disease [CD] as well as disease activity in ulcerative colitis [UC]. Ex vivo immunophenotyping revealed that CD4+ and CD8+ T cell subsets were not substantially altered in vitD-deficient vs vitD-sufficient patients while regulatory T cell frequencies were reduced in UC and non-smoking CD patients with vitD deficiency. However, normalization of serum vitD concentrations in previously deficient CD patients resulted in significantly reduced frequencies of CD4+ T cells producing IFNγ, IL-17 and IL-22. Conclusion vitD exerts profound anti-inflammatory effects on peripheral and intestinal CD4+ and CD8+ T cells of IBD patients in vitro and inhibits TH1 and TH17 cytokine production in CD patients in vivo.

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