CD4+CD26 - T Cell Population in Classical Hodgkin Lymphoma Displays a Distinctive Regulatory T Cell Population.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 384-384
Author(s):  
Yue Ma ◽  
Lydia Visser ◽  
Tjasso Blokzijl ◽  
Geert Harms ◽  
Cigdem Atayar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Hodgkin Lymphoma ◽  
Regulatory T Cell ◽  
T Cell Subsets ◽  
Mrna Levels ◽  
Classical Hodgkin Lymphoma ◽  
Cell Type ◽  
Activated T Cell

Abstract Introduction: Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) are surrounded by a majority of infiltrating reactive cells, which mainly consists of CD4+ T cells. These T cells express several activation associated surface markers but lack expression of the T cell co-stimulatory molecule CD26. Little is known about the significance of these rosetting CD4+CD26- T cells. Methods: To characterize these T cells, CD4+CD26- and CD4+CD26+ T cells were sorted from lymph node cell suspensions from 7 cHL and 5 reactive lymph nodes (LN). Of 5 HL cases and 3 lymph nodes, parts of the cells were stimulated with PMA/ionomycin to get activated T cell subsets. mRNA profiles of activated and non-activated T cell populations were evaluated with quantitative RT-PCR for 46 selected genes. Results: We observed a higher percentage of CD4+CD26- T cells in cHL compared to reactive LN. For the non-activated T cell subsets, CD4+CD26- T cells in cHL showed higher mRNA levels of IL2RA, CTLA4, TNFRSF4 and CCR4 compared to LN. Moreover, these cells displayed low or no expression of the Th1 or Th2 related cytokines IL2, IFNγ, IL13, IL12B, IL4, IL5 and the chemoattractant receptor GPR44. Overall, the profiling results support a regulatory T (Treg) cell type for the CD4+CD26- T cells in cHL. Besides Tregs, Th17 cells may exist in cHL based on the significantly higher IL17 mRNA level for both the CD26- and CD26+ T cells in cHL than in LN. Upon activation, the lack of up-regulation of mRNA levels of most cytokine genes (IFNγ, IL2, IL8, IL21, IL17, IL13, IL12A and IL4) indicated an anergic character for the CD4+CD26− subset in cHL. Conclusion: A high proportion of CD4+CD26− T cells is characteristic for cHL. No evidence for a Th1 or Th2 cell type is found for these cells but they display a regulatory T cell phenotype. Anergy fits with the regulatory T cell profile of these cells, probably explaining the immunosuppressive mechanism involved in cHL.

scholarly journals Nodular Lymphocyte Predominant Hodgkin Lymphoma - A Retrospective Immunohistochemical Study of Patients in Bangalore, Karnataka

2021 ◽  
Vol 8 (23) ◽  
pp. 1966-1969
Author(s):  
Shankar Anand ◽  
Akshatha C ◽  
Libin Babu Cherian ◽  
Ramachandra C
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Hodgkin Lymphoma ◽  
Classical Hodgkin Lymphoma ◽  
Double Positive ◽  
Cervical Lymph Nodes ◽  
Histiocytic Cell ◽  
Immunohistochemical Markers ◽  
Lp Cells

BACKGROUND The term Hodgkin’s lymphoma includes classical Hodgkin lymphoma (CHL) and the less common nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). NLPHL is a B cell neoplasm usually characterised by nodular or follicular and diffuse proliferation of small lymphocytes with single scattered large neoplastic cells (LP/L&H/Popcorn cells). NLPHL accounts for 10 % of all Hodgkin lymphoma. METHODS This is a retrospective study. Histopathology slides and blocks of 24 cases of nodular lymphocyte predominant Hodgkin lymphoma were collected from the archives of histopathology from 2011 to 2015. The immunohistochemistry slides of the corresponding histopathology cases were also assembled. Both the slides were reviewed by three expert onco-pathologists and IHC markers were studied and compared. RESULTS Patients were mostly young between 20 and 40 years (16 / 24, 66.67 %). There was a distinct male preponderance (20 / 24, 83.3 %). Most cases involved cervical, axillary or inguinal lymph nodes, with cervical lymph nodes being the most common (13 / 24, 54 %). It was found that CD45, CD20, CD79a and PAX5 staining highlighted the LP cells in all twenty-four cases, while OCT - 2 and BOB - 1 were highlighted in twenty-three cases (95.8 %), which was statistically significant. CD3 and CD5 IHC staining on T cell rosettes and background reactive T cells were examined, and it was seen that CD3 expression was far more consistent than CD5 expression in T cell rosettes and reactive T cells. Also, it was seen that, those cases which were double positive for CD3 and CD5 constitutes only eight cases (8 / 24, 33.3 %). CONCLUSIONS CD3 is a more consistent marker than CD5 in demonstrating surrounding reactive T cells in NLPHL. CD45, PAX5, CD20, BOB - 1 and OCT - 2 are consistent immunohistochemical markers of LP cells. KEYWORDS Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL), Classical Hodgkin Lymphoma (CHL), Cluster Differentiation (CD), Lymphocyte Predominant Cells (LP Cells), Lymphocyte and Histiocytic Cell (L & H Cell)

Identification and Purification of Hodgkin Cells from Lymph Nodes Involved by Classical Hodgkin Lymphoma by Flow Cytometry and Flow Cytometric Cell Sorting.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2262-2262
Author(s):  
Jonathan R. Fromm ◽  
Steven J. Kussick ◽  
Brent L. Wood
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Hodgkin Lymphoma ◽  
Cell Sorting ◽  
Classical Hodgkin Lymphoma ◽  
Tissue Sections ◽  
Hla Dr ◽  
Blocking Antibodies

Abstract The diagnosis of classical Hodgkin lymphoma (CHL) has historically been made in tissue sections, as attempts to identify the neoplastic Hodgkin and Reed-Sternberg (HRS) cells of CHL by flow cytometry (FC) have been largely unsuccessful. As HRS cells are known to be ringed (“rosetted”) by benign/reactive T cells, we hypothesized that in cell suspensions the HRS will be bound to T cells (forming T cell rosettes), and that consequently the rosettes would have a composite T-cell/HRS immunophenotype by FC (CD3+/CD15+/CD20−/CD30+/CD45+). We further hypothesized that specific antibodies to the adhesion molecules known to be involved in T cell/HRS cell binding (CD2 and LFA-1 on the T cell, and CD54 and CD58 on the HRS cell) might result in “naked” (unbound) HRS cells, enabling us to use FC to identify HRS cells with the expected immunophenotype (CD3−/CD15+/CD20−/CD30+/CD45−). Our initial FC studies of the HRS cell line L1236 demonstrated that CD15, CD30, CD40, CD71, CD86, CD95, and HLA-DR, but not CD3 or CD20, were brightly expressed on these cells and may be useful in identification of HRS in authentic cases of CHL involving lymph nodes. In mixing experiments, L1236 cells spontaneously bound normal T cells, analogous to T cell rosetting of HRS cells in CHL; these interactions could be blocked specifically using a cocktail of unlabeled antibodies to CD2, LFA-1, CD54, and CD58. Among 27 lymph nodes involved by CHL, this novel FC method, in which 250,000 to 500,000 total lymph node cells were evaluated, and in which up to ten cellular antigens were assessed simultaneously, enabled HRS cells to be identified in 89% of cases. 82% of these cases demonstrated interactions between HRS cells and T cells that could be disrupted with blocking antibodies. None of 29 non-CHL neoplasms, and none of 23 reactive lymph nodes, demonstrated HRS populations by FC. The proportions of cases where the HRS population showed expression of CD15, CD30, CD40, CD71, CD86, CD95, and HLA-DR, and absence of CD3 and CD20 was similar to that described previously in tissue sections by immunohistochemistry. Interestingly, in contrast to the findings in tissue sections, by FC the non-rosetted HRS cells of most CHL cases (73%) demonstrated detectable expression of CD45, usually at a low level. Finally, cell sorting experiments confirmed that (1) populations identified by FC have the cytomorphology of HRS cells, (2) HRS/T cell rosettes can be detected by FC, and (3) these rosettes can disrupted by the blocking antibody cocktail. This FC technique offers a potential alternative to immunohistochemistry in confirming the diagnosis of CHL and, through cell sorting, provides a means of rapidly purifying HRS cells.

scholarly journals Effects of Vitamin D Supplementation on CD4+ T Cell Subsets and mTOR Signaling Pathway in High-Fat-Diet-Induced Obese Mice

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 796
Author(s):  
Jeong Hee An ◽  
Da Hye Cho ◽  
Ga Young Lee ◽  
Min Su Kang ◽  
So Jeong Kim ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cells ◽  
T Cell ◽  
Vitamin D Supplementation ◽  
Mtor Pathway ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Dietary Vitamin ◽  
Mrna Levels ◽  
High Fat

Obesity is associated with an impaired balance of CD4+ T cell subsets. Both vitamin D and obesity have been reported to affect the mTOR pathway. In this study, we investigated the effects of vitamin D on CD4+ T cell subsets and the mTOR pathway. Ten-week-old male C57BL/6 mice were divided into four groups and fed diets with different fat (control or high-fat diets: CON or HFD) and vitamin D contents (vitamin D control or supplemented diets: vDC or vDS) for 12 weeks. T cells purified by negative selection were stimulated with anti-CD3/anti-CD28 mAbs and cultured for 48 h. The percentage of CD4+IL-17+ T cells was higher in the vDS than vDC groups. The CD4+CD25+Foxp3+ T cells percentage was higher in HFD than CON groups. The phospho-p70S6K/total-p70S6K ratio was lower in vDS than vDC, but the phospho-AKT/total-AKT ratio was higher in vDS than vDC groups. Hif1α mRNA levels were lower in vDS than vDC groups. These findings suggest HIF1α plays an important role in vitamin-D-mediated regulation of glucose metabolism in T cells, and dietary vitamin D supplementation may contribute to the maintenance of immune homeostasis by regulating the mTOR pathway in T cells.

CD4+ T cells are essential for the development of destructive thyroiditis induced by anti–PD-1 antibody in thyroglobulin-immunized mice

2021 ◽  
Vol 13 (593) ◽  
pp. eabb7495
Author(s):  
Yoshinori Yasuda ◽  
Shintaro Iwama ◽  
Daisuke Sugiyama ◽  
Takayuki Okuji ◽  
Tomoko Kobayashi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Mononuclear Cells ◽  
Critical Role ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Histopathological Analysis ◽  
Activated T Cells ◽  
Cervical Lymph Nodes

Immune-related adverse events induced by anti–programmed cell death–1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4+ T cells and partially prevented by depleting CD8+ T cells. The frequencies of central and effector memory CD4+ T cell subsets and the secretion of interferon-γ after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4+ T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4+ T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4+ T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4+ T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE.

Abstract 184: Pressure Overload Activates Left Ventricular (LV) Intramyocardial Vascular Endothelial Cells and induces T Cell Infiltration into the LV

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Pilar Alcaide ◽  
Anna Grodecki-Pena ◽  
Andrew Knapp ◽  
Tanya Kershaw ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Vascular Endothelium ◽  
Pressure Overload ◽  
Left Ventricular ◽  
T Cell Subsets ◽  
Mrna Levels ◽  
Flow Conditions ◽  
Cell Recruitment

Left ventricular dysfunction and Heart Failure (HF) are associated with systemic inflammation with clinical data showing that HF patients have higher levels of circulating pro-inflammatory cytokines. Recruitment of circulating T cells to tissues across the vascular endothelium is a key event in the inflammatory response, but whether it plays a role in the heart in HF is unknown. We hypothesized that pressure overload induced HF activates cardiac endothelial cells resulting in T cell recruitment into the left ventricle (LV). Using transverse aortic constriction (TAC), quantitative flow cytometry, immunohistochemistry, qPCR and real time live cell videomicroscopy, we examined mRNA and protein expression levels of endothelial cell adhesion molecules and the presence of T cell infiltrates in the LV in vivo , and also studied the T cell interactions with primary mouse heart endothelial cells (MHEC) under flow conditions in vitro , comparing Sham and TAC operated mice (6-10/group) during the course of HF. 48h after TAC, in the pre-hypertrophic state, no differences were observed in the recruitment of T cells in the LV. Interestingly, two and four weeks after TAC, when mice developed LVH and LV dysfunction (Fractional Shortening 25±13%), E-Selectin, VCAM-1 and ICAM-1 mRNA levels were significantly upregulated in the LV as compared to Sham mice (2.3, 2.8 and 4 fold, respectively), with notable enhancement of endothelial ICAM-1 protein levels in the LV intramyocardial vessels, and T cells infiltrated in the LV in response to TAC (P≤0.05 TAC vs Sham). Furthermore, T cells isolated from mice 2 and 4 weeks after TAC adhered to MHEC under flow conditions in significantly higher numbers than T cells from Sham mice (P≤0.01 TAC vs Sham). Systemically, the frequency of three different T cell subsets in the peripheral lymphoid organs was increased in TAC vs Sham mice, indicating activation of the adaptive immune response to pressure overload. Taken together, our studies indicate that activation of the heart vascular endothelium occurs in response to pressure overload resulting in T cell recruitment into the LV. Further studies will be needed to determine in the extent to which T cell recruitment into the heart contributes to the pathogenesis of HF.

Continuous CD4+ T Cell Lines Derived From the Classical Hodgkin Lymphoma Microenvironment: A Challenge to the Assumption of Anergy,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3645-3645
Author(s):  
Paul Greaves ◽  
Sameena Iqbal ◽  
David C Taussig ◽  
John G. Gribben
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Culture Media ◽  
Tissue Bank ◽  
Lymphocyte Culture ◽  
Classical Hodgkin Lymphoma ◽  
T Cell Lines ◽  
Reactive Node

Abstract Abstract 3645 Introduction: The bulk of the tumour infiltrate in classical Hodgkin lymphoma (CHL) is composed of immune cells, predominantly CD4+ T cells, with the malignant Hodgkin Reed Sternberg cell (HRS) representing <1% of cells. The lymphoid microenvironment has been described as anergic and hypoproliferative with suppressive properties (Marshall et al. Blood 2004 103:1755–62) but the functional significance of this is unclear. This study set out to examine the proliferative capacity and phenotype of T cells derived from CHL-diagnostic lymph node tissue taken at diagnosis. Method: Frozen single cell suspensions (SCS) from 6 patients were selected from the tissue bank of our Institute. T cell growth-augmenting and/or Th2 polarising cytokines were added in various combinations (IL2, IL4 only, IL2+4 or no added cytokine) to SCS-derived cells in 96 well plates at 0.3 × 106 cells per well in 200mcl of optimized lymphocyte culture media. No CD4+ enrichment step was carried out: all recovered cells were plated at baseline to maintain potential interactions between CD4+ cells and other cells, and no mitogen or T-cell receptor-stimulating or costimulating agents were added at any point. As controls, SCS derived from normal tonsil, and ÔreactiveÕ lymph nodes (n=4) (confirmed by histological report at the time of diagnosis) were also plated. Plates were examined daily for cell/colony morphology to estimate growth and split with fresh media and cytokines once every 7 days, with estimated proliferation (by haemocytometry) plotted. Cultures were assessed at baseline, 10 days, 28 days, 50 days and 100 days. Results: Proliferation, based on formation of discrete colonies and blastoid cell morphology, occurred in the majority of wells by day 7 in all CHL-derived cultures, and in a minority of wells, and to a lesser extent in all control cultures. CHL-derived T cells from one patient continue to expand after 200 days, doubling every 3–5 days, while the other 5 continue after 50–100 days. In contrast, no tonsil or reactive node-derived T cells survived beyond 50 days and none showed a net expansion in cell numbers. Growth was superior in the IL2+4 and IL2-only conditions, with no growth in the media-only or IL4-only conditions. The most favorable condition was with the addition of IL2+4. By day 21 a net increase in CHL-derived T cells was apparent, but not in any control T cell populations (Figure). At baseline, composition of the CHL-derived cells revealed a majority of CD3+ cells as expected, of which 60–80% were CD4+ and the remainder CD8+. By D21 the CD4+ component had outgrown all other cells in the CHL-derived cultures, being CD3+CD4+CD45RO+ consistent with antigen-experienced T helper cells, while all tonsil and reactive node-derived cells were CD8+CDRO+. Markers of central memory (CCR7 & CD62-L), Th2 (CCR4 and IL4), Treg (FOXP3 and CD25) and anergy (CD57) were absent after expansion, while markers of activation were upregulated (CD28, CD27, CD69, CD40L, CD30 & CD95). This phenotype persisted in the ongoing T cell lines. Conclusions: The CD4+ compartment of the CHL microenvironment contains a primed subset of cells capable of massive expansion without further mitogenic stimulation and of generating cytokine-dependent continuous cell lines with an antigen-experienced, activated phenotype. This challenges the assumption of T cell anergy and hypoproliferation in the tissue microenvironment of CHL. We are currently assessing the function and anti-tumor specific or tumor supportive nature of these T cells. Disclosures: Gribben: Roche: Honoraria; Celgene: Honoraria; GSK: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria.

scholarly journals The Tumor Microenvironment of Nodular Lymphocyte Predominant Hodgkin Lymphoma Is a Unique Immunobiological Entity Distinct from Classical Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4123-4123
Author(s):  
Jay Gunawardana ◽  
Karolina Bednarska ◽  
Soi C Law ◽  
Justina Lee ◽  
Muhammed Bilal Sabdia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Host Immunity ◽  
Immune Checkpoints ◽  
Classical Hodgkin Lymphoma ◽  
Advisory Committees ◽  
Immune Effector

Abstract There is proven pre-clinical and clinical efficacy of mono or combinatorial immune strategies to boost host anti-lymphoma immunity, with classical Hodgkin Lymphoma (cHL) seen as the 'poster child'. Approaches include blockade of immune-checkpoints on exhausted tumor-specific T-cells (via mAb blockade of PD-1, TIM3, LAG3, TIGIT or their ligands), activation of T-cells via mAbs agonistic to CD137, and finally modulation of FOXP3, CTLA-4 and/or LAG3 regulatory T-cells (Tregs) or immunosuppressive tumor-associated macrophages (TAMs). In contrast, studies characterizing the circulating and intra-tumoral microenvironment (TME) of the distinct but rare CD20+ Hodgkin Lymphoma entity (5-8% of HL), Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL), are minimal. Furthermore, to our knowledge no functional profiling studies comparing the host immunity of NLPHL with cHL has been performed. We compared host immunity in 29 NLPHL patients, 30 cHL patients and 10 healthy individuals, with a focus on pertinent and clinically actionable immune parameters. Paraffin-embedded tissue and paired (pre- and post-therapy) peripheral blood mononuclear cells samples were interrogated by digital multiplex hybridization (Nanostring Cancer Immune Profiling Panel) and flow cytometry. Although cytotoxic T-cell gene counts (CD8a, CD8b) were similar, compared to cHL there were higher levels of the immune effector activation marker CD137 (gene counts 439 vs. 287; P<0.01). Consistent with this, CD4 and the Treg markers LAG3, FOXP3 and CTLA-4 were lower in NLPHL (2-4 fold lower, all P<0.05), with no difference in T-helper cell activation markers CD40L and CD30L seen between tumors. TAMs and dendritic cell markers MARCO, CD36, CD68, CD163, COLEC12 and CD11b were all lower in NLPHL than cHL (all P<0.05). In line with the known 'rossette' formed around LP cells by PD-1+ T-lymphocytes, we observed strikingly elevated PD-1 and the other T-cell checkpoints TIM3 and TIGIT in NLPHL (all 2-3 fold, P<0.001). However, in line with the known gene amplification of PD-L1 on HRS cells and its presence on TAMs, gene counts of this checkpoint ligand were 2-fold higher in cHL (P<0.001). Flow cytometry profiling of immune subsets in peripheral blood showed findings consistent with findings in the TME. Specifically, there was elevation of multiple exhaustion markers within CD4, CD8, and NK immune effector cells, with a striking proportion of highly anergic dual-LAG3/PD-1 positive CD8+ T-cells. Also there was elevation of immune-suppressive monocyte/macrophages in cHL relative to NLPHL. Relative to healthy lymph nodes, there was prominent up-regulation of a range of T-cell associated exhaustion markers in both NLPHL and cHL, indicating dysregulated priming of effector immune responses and host immune homeostasis. Comparison between NLPHL and cHL illustrated that NLPHL had a myriad of features that marked its intratumoral TME as a unique immunobiological entity typified by elevated immune checkpoint markers and T-cells with a highly anergic phenotype. Put together, these findings indicate that distinct immune evasion mechanisms are operative within the TME of NLPHL, including markedly higher levels of multiple immune-checkpoints relative to cHL. In contrast, Treg subsets and immune-suppressive monocyte/macrophages were relatively lower than that seen in cHL. T-cells frequently had dual immune-checkpoint expression. The findings from this study provides a compelling pre-clinical rationale for targeting PD-1 or combinatory checkpoint inhibition in NLPHL and sets the basis for future 'chemo-free' rituximab + checkpoint inhibitor clinical trials. Disclosures Tobin: Amgen: Other: Educational Travel; Celgene: Research Funding. Birch:Medadvance: Equity Ownership. Keane:Takeda: Other: Educational Meeting; BMS: Research Funding; Roche: Other: Education Support, Speakers Bureau; Celgene: Consultancy, Research Funding; Merck: Consultancy. Gandhi:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Clonal Vγ6+Vδ4+ T cells promote IL-17–mediated immunity against Staphylococcus aureus skin infection

2019 ◽  
Vol 116 (22) ◽  
pp. 10917-10926 ◽  
Author(s):  
Mark C. Marchitto ◽  
Carly A. Dillen ◽  
Haiyun Liu ◽  
Robert J. Miller ◽  
Nathan K. Archer ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Skin Infection ◽  
Cell Subset ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Rna Seq ◽  
Host Defense Peptides

T cell cytokines contribute to immunity against Staphylococcus aureus, but the predominant T cell subsets involved are unclear. In an S. aureus skin infection mouse model, we found that the IL-17 response was mediated by γδ T cells, which trafficked from lymph nodes to the infected skin to induce neutrophil recruitment, proinflammatory cytokines IL-1α, IL-1β, and TNF, and host defense peptides. RNA-seq for TRG and TRD sequences in lymph nodes and skin revealed a single clonotypic expansion of the encoded complementarity-determining region 3 amino acid sequence, which could be generated by canonical nucleotide sequences of TRGV5 or TRGV6 and TRDV4. However, only TRGV6 and TRDV4 but not TRGV5 sequences expanded. Finally, Vγ6+ T cells were a predominant γδ T cell subset that produced IL-17A as well as IL-22, TNF, and IFNγ, indicating a broad and substantial role for clonal Vγ6+Vδ4+ T cells in immunity against S. aureus skin infections.

High Proportions of CD4+CD25hi T Cells Pretransplant Correlate with Worse Overall Survival after Stem Cell Transplant.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3126-3126
Author(s):  
Adria Prieto-Hinojosa ◽  
J. Alejandro Madrigal ◽  
Bronwen E. Shaw ◽  
Neema P. Mayor ◽  
Stephen G.E. Marsh ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Regulatory Function ◽  
Cell Transplant ◽  
Mrna Levels ◽  
Foxp3 Mrna

Abstract Regulatory cells may have a modulatory effect on alloreactive phenomena following hematopoietic stem cell transplantation (HSCT), although their role in this setting in patients remains controversial. We have analysed the effect of pre-conditioning peripheral blood levels of T-regs on the outcome of 89 adult patients undergoing HLA-identical (10/10) unrelated donor (UD)-HSCT. Allografts were T-cell depleted with Alemtuzumab, which has been described to spare T-regs from, and we found that higher proportion of CD4+CD25hi T-cells correlated with worse survival (p=0.002). This higher proportion also correlated with higher incidence of relapse (p=0.0274) and with higher incidence of chronic (c) GvHD (p=0.033) but not with the incidence of aGvHD. Regulatory T cells (T-regs) are a naturally occurring regulatory population of CD4+CD25hi T-cells known to express the transcription repressor FoxP3 and to produce anti-inflammatory cytokines such as TGFβ and may therefore affect patient survival. We analyse the profile of the CD4+CD25hiT cells in our cohort. In our healthy donor control group (n=30), CD4+CD25hi-expression associated with both, FoxP3 mRNA-levels (r=0.649; p=0.001) and TGFβ production (r=0.912; p<0.001), as previously described for T-regs. In preconditioning patient samples however, CD4+CD25hi-expression had a strong correlation with TGFβ regulatory cytokine production (r=0.863; p<0.001) as expected. However, FoxP3 mRNA-expression correlated neither with the CD4+CD25hi T-regs phenotype (r=0.280; p=0.040), nor with the production of TGFβ (r=0.229; p=0.156), and appeared not be an accurate marker for regulatory T-cell function in this patient setting. In addition, an inverse correlation with TNFα expression (r=−0.458 p<0.001) was found that may argue that the CD4+CD25hi cells represent a true regulatory population and not activated cells. This suggests either that activated cells that are not expressing FOXP3 might be included in the CD4+CD25hi population or that CD4+CD25loFOXP3+ cells have not acquire the regulatory function (i.e. they are not expressing TGFβ). In summary, CD4+CD25hi Regulatory T cells may have an impact suppressing allo-responses against the tumour, decreasing the overall survival by increasing the rates of relapse. Although, in mice CD4+CD25hi population have been clearly identified by the expression of the FOXP3, which encodes a transcription repressor, in humans this remains controversial, where FOXP3 expression is not exclusive of the CD4+CD25hi population. Relying on the expression of CD4+CD25hi and FOXP3 in patients is insufficient to determine regulatory T cell numbers and suggests that other parameters of regulatory function should be taken in to account.

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