Commensal Microbiota Promote Lung Cancer Development via γδ T Cells.

γδ T cells are situated at barrier sites and guard the body from infection and damage. However, little is known about their roles outside of host defense in nonbarrier tissues. Here, we characterize a highly enriched tissue-resident population of γδ T cells in adipose tissue that regulate age-dependent regulatory T cell (Treg) expansion and control core body temperature in response to environmental fluctuations. Mechanistically, innate PLZF+ γδ T cells produced tumor necrosis factor and interleukin (IL) 17 A and determined PDGFRα+ and Pdpn+ stromal-cell production of IL-33 in adipose tissue. Mice lacking γδ T cells or IL-17A exhibited decreases in both ST2+ Treg cells and IL-33 abundance in visceral adipose tissue. Remarkably, these mice also lacked the ability to regulate core body temperature at thermoneutrality and after cold challenge. Together, these findings uncover important physiological roles for resident γδ T cells in adipose tissue immune homeostasis and body-temperature control.

γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis.

Dysregulated IL-23/IL-17 responses have been linked to psoriatic arthritis and other forms of spondyloarthritides (SpA). RORγt, the key Thelper17 (Th17) cell transcriptional regulator, is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and γδ-T cells, but their contribution to SpA is still unclear. Here we describe the presence of particular RORγt+T-betloPLZF- iNKT and γδ-hi T cell subsets in healthy peripheral blood. RORγt+ iNKT and γδ-hi T cells show IL-23 mediated Th17-like immune responses and were clearly enriched within inflamed joints of SpA patients where they act as major IL-17 secretors. SpA derived iNKT and γδ-T cells showed unique and Th17-skewed phenotype and gene expression profiles. Strikingly, RORγt inhibition blocked γδ17 and iNKT17 cell function while selectively sparing IL-22+ subsets. Overall, our findings highlight a unique diversity of human RORγt+ T cells and underscore the potential of RORγt antagonism to modulate aberrant type 17 responses.

https://biblio.ugent.be/publication/8601543/file/8601546.pdf

RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients

T cell lineages are defined by specialized functions and differential expression of surface antigens, cytokines and transcription factors Conventional CD4+ and CD8+ T cells are the best studied of the T cell subsets, but 'unconventional' T cells have emerged as being more abundant and influential than has previously been appreciated Key subsets of unconventional T cells include natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells and γδ T cells; collectively, these make up ~10% of circulating T cells, and often they are the majority of T cells in tissues such as the liver and gut mucosa Defects and deficiencies in unconventional T cells are associated with autoimmunity, chronic inflammation and cancer, so it is important to understand how their development is regulated In this Review, we describe the thymic development of NKT cells, MAIT cells and γδ T cells and highlight some of the key differences between conventional and unconventional T cell development

Thymic development of unconventional T cells: how NKT cells, MAIT cells and γδ T cells emerge

Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-γ+ γδ T cells were almost exclusively dependent on glycolysis, IL-17+ γδ T cells strongly engaged oxidative metabolism, with increased mitochondrial mass and activity. These distinct metabolic signatures were surprisingly imprinted early during thymic development and were stably maintained in the periphery and within tumors. Moreover, pro-tumoral IL-17+ γδ T cells selectively showed high lipid uptake and intracellular lipid storage and were expanded in obesity and in tumors of obese mice. Conversely, glucose supplementation enhanced the antitumor functions of IFN-γ+ γδ T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector γδ T cells and their manipulation in cancer immunotherapy.

https://hal.archives-ouvertes.fr/hal-03121669/document

Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments

Expression of the transcription factor Zbtb1 is required for normal lymphoid development. We report in the present study that Zbtb1 maintains genome integrity in immune progenitors, without which cells undergo increased DNA damage and p53-mediated apoptosis during replication and differentiation. Increased DNA damage in Zbtb1-mutant (ScanT) progenitors was due to increased sensitivity to replication stress, which was a consequence of inefficient activation of the S-phase checkpoint response. Increased p53-mediated apoptosis affected not only lymphoid but also myeloid development in competitive bone marrow chimeras, and prevention of apoptosis by transgenic Bcl2 expression and p53 deficiency rescued lymphoid as well as myeloid development from Zbtb1-mutant progenitors. Interestingly, however, protection from apoptosis rescued only the early stages of T cell development, and thymocytes remained arrested at the double-negative 3 developmental stage, indicating a strict requirement of Zbtb1 at later T cell developmental stages. Collectively, these results indicate that Zbtb1 prevents DNA damage in replicating immune progenitors, allowing the generation of B cells, T cells, and myeloid cells.

Zbtb1 Safeguards Genome Integrity and Prevents p53-Mediated Apoptosis in Proliferating Lymphoid Progenitors

Dear Editor, The BTB-ZF (broad-complex, tramtrack and brica-brac–zinc finger) proteins play essential roles in the development of the immune system. Transcriptional repressor Zbtb1is one of the BTB-ZF members essential for lymphocyte development and NKp46 ROR-gamma-T innate lymphoid cell (ILC3) development. Although the mechanisms by which Zbtb1 promote lymphoid development have been investigated, many questions are still unsolved, especially for T-cell development. T cells require IL-7 signalling throughout their life, including maturation, differentiation and survival in peripheral lymphoid tissues. Both B and T cells developmental block were seen in the mice deficient for IL-7 receptor a-chain (IL-7Ra). Interestingly, enforced expression of Bcl-2 restored T-cell development but not B cell in IL-7Ra / mice, however, Bcl-2 overexpression in the ScanT (Zbtb1 mutant) mice restored B cell but only early T-cell development. In this study, the interplay between Zbtb1 and IL-7Ra was dissected during T-cell development. At first we decided to evaluate the regulation of Zbtb1 expression by IL-7Ra signalling during T-cell development in vitro. We chose D1 cell line as a simplified research model, which was an IL-7 (interleukin7)-dependent thymic cell line derived from a p53 / mouse. According to the surface maker expression by flow cytometry, D1 is a DN1(double negative, stage 1)-like cell line, which is CD44CD25 IL7Ra(Figure S1A). D1 cells were maintained in complete medium with 10 ng/mL IL-7. To test the impact of IL-7Ra signalling on Zbtb1 expression, D1 cells were starved overnight by IL-7 deprivation, and then re-stimulated with 10 ng/mL IL-7. The Zbtb1 mRNA level reached the peak after IL-7 deprivation overnight. However, the Zbtb1 transcripts down-regulated after IL-7 re-stimulation, with the lowest level at 4 hours adding IL-7 (Figure 1A). In order to investigate the effect of IL-7Ra signalling on Zbtb1 expression in vivo, we utilized the mice deficient for IL-7Ra and IL-7Ra / compound with IL-7Ra transgene under the control of human CD2 promoter (T cell-specific). We sorted double positive (DP), CD4 single positive (SP) and CD8SP thymocytes from wild-type C57BL/6 and IL-7Ra mutant mice mentioned above (Figure 1B), then performed RT-qPCR assay. We found Zbtb1 expression level were elevated in all cell types in IL-7Ra / compared to wild-type. However, Zbtb1 transcripts were down-regulated in all cell types of mice with IL-7Ra / compound with IL-7Ra transgene. These data suggest that the transcription of Zbtb1 can be negatively regulated by IL-7Ra signalling. Next we investigated the effect of Zbtb1 on IL-7Ra expression. We transduced the D1 cells with either retroviral vector Mir-CTR or Zbtb1-overexpressing retrovirus, and sorted the GFP cells to establish the stable cell line (Figure 1D). The Zbtb1 overexpression in Mir30-P2A-Zbtb1 stable cell line was confirmed by RT-qPCR (Figure 1E). We deprived IL-7 from culture medium of D1 cells overnight, re-stimulated with different concentration of IL-7, and then analysed surface IL-7Ra level at different time post-stimulation. We found that Zbtb1 overexpression can down-regulate IL-7Ra under sub-optimal IL-7 concentration (1 ng/mL) (Figure 1F,G). In order to address the impact of Zbtb1 on IL-7Ra during T-cell development in vivo, we gated different sub-population in thymocytes

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.13663

Reciprocal suppression between Zbtb1 expression and IL‐7Rα signalling during T‐cell development

Dear editors, Innate-like T-cells can be placed in-between the adaptive and innate immune systems. The mechanisms that determine the differentiation of innate-like T-cells is not completely understood. Innate-like T cells include invariant Natural Killer T-cells (iNKT), which express a αβTCR, and γδNKT cells, which express a γδTCR corresponding to Vδ6.3 and Vγ1.1. Previous study showed that Zbtb16 (PLZF) was necessary for the acquisition of an innate-like phenotype in iNKT and γδNKT cells. Absence of PLZF severely impairs iNKT cell development, leading to a reduction of iNKT cell numbers. iNKT cells that develop in PLZF-deficient mice have a naive phenotype, lost the ability to co-express IL4 and IFN-γ, lost the ability to migrate to the liver and preferentially located to lymph nodes. Reciprocally, transgenic PLZF expression was sufficient to confer an effector phenotype to T-cells and similar migratory properties as iNKT cells. This phenotypic conversion occurred during development and in the absence of agonist selection, indicating that PLZF expression was sufficient to alter the phenotypic characteristics of T-cells. γδΝΚT-cells expressing Vγ1.1 and Vδ6.3/6.4 share characteristics of iNKT cells, and in PLZF-deficient mice Vγ1.1 Vδ6.3 γδT-cells were still present in reduced numbers. Furthermore, our previous study demonstrated that PLZF controled the development of fetal-derived IL-17 Vγ6 γδT-cells. However, how PLZF expression is regulated and how it exerts these functions is not clearly understood. We, therefore, decided to focus our efforts in understanding how PLZF expression provides an innate-like phenotype to iNKT cells and γδNKT cells. At first we decided to evaluate the regulation of PLZF expression during T-cell development by PLZF-GFP reporter mice. Briefly, the reporter mice were generated by control the expression of transgene eGFP with PLZF regulatory elements in a modified bacterial artificial chromosome. We observed GFP fluorescence in iNKT cells (Fig. S1A). PLZF expression was low in early thymic progenitors (ETP), was slightly upregulated at the DN2a stage of development and turned off after T-cell specification at the DN3, DN4, and DP positive stages (Fig. S1B). We observed that contrarily to adult mice, PLZF expression was abundant in fetal thymocytes at every developmental stage (Fig. S1C). In light of the abundant expression of PLZF that we observed in the fetal thymus, we wanted to evaluate if fetal HSC may be biased to differentiate towards innate-like iNKT and γδNKT cells as compared to adult HSCs. We tested this by performing mixtures of congenic Fetal liver and Adult Bone Marrow chimeras and analyzed if iNKT and γδNKT cells were preferentially derived from fetal or adult precursors. We observed that there was no preferential bias of fetal HSCs to give rise to innate-like cells under these conditions (Fig. S1D–F). We next tested the possibility of innate-like cells being derived from fetal precursors by performing transplants of neonatal day 1 thymus under the kidney capsule of congenic hosts. In this system, cells from the donor transplanted thymus are progressively replaced by differentiating thymocytes derived from host HSCs. Therefore,

/pdf/plzf-play-as-an-indirect-facilitator-of-thymic-retention-for-5fcmfn8rx9.pdf

PLZF play as an indirect facilitator of thymic retention for the innate-like T-cells to aquire innate-like functions

Expression of promyelocytic leukemia zinc finger (PLZF) protein directs the effector differentiation of invariant NKT (iNKT) cells and IL-4(+) γδ NKT cells. In this study, we show that PLZF is also required for the development and function of IL-17(+) γδ T cells. We observed that PLZF is expressed in fetal-derived invariant Vγ5(+) and Vγ6(+) γδ T cells, which secrete IFN-γ and IL-17, respectively. PLZF deficiency specifically affected the effector differentiation of Vγ6(+) cells, leading to reduced numbers of mature CD27(-)CD44(+) phenotype capable of secreting IL-17. Although PLZF was not required for Vγ5(+) γδ T cells to develop, when these cells were reprogrammed into IL-17-secreting cells in Skint-1 mutant mice, they required PLZF for their effector maturation, similarly to Vγ6(+) γδ T cells. The impaired effector differentiation of PLZF-deficient Vγ6(+) γδ T cells was not due to increased apoptosis and it was related to reduced proliferation of immature CD27(+)CD44(-) Vγ6(+) γδ T cells, which was required for their differentiation into mature CD27(-)CD44(+) IL-17-secreting cells. Thus, the present study identifies that PLZF function is not restricted to NKT or IL-4(+) T cells, but it also controls the development of IL-17(+) γδ T cells.

/pdf/plzf-controls-the-development-of-fetal-derived-il-17-vg6-gd-lhi4zzewwu.pdf

PLZF Controls the Development of Fetal-Derived IL-17+Vγ6+ γδ T Cells

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Zbtb1 Safeguards Genome Integrity and Prevents p53-Mediated Apoptosis in Proliferating Lymphoid Progenitors

Reciprocal suppression between Zbtb1 expression and IL‐7Rα signalling during T‐cell development

PLZF play as an indirect facilitator of thymic retention for the innate-like T-cells to aquire innate-like functions

PLZF Controls the Development of Fetal-Derived IL-17+Vγ6+ γδ T Cells