Memory CD8+ T cells induced upon immunization exhibit improved functional features that contribute to protection of immunized hosts. Although both cognate antigen recognition and inflammation are ...important for memory CD8+ T cell reactivation, the relative contribution of these factors and the cell types providing these signals in vivo are poorly defined. Here, we show that Ly6C+CCR2+ inflammatory monocytes, a subset of monocytes, largely orchestrate memory CD8+ T and NK lymphocytes activation by differentiating into interleukin-18 (IL-18)- and IL-15-producing cells in an inflammasome and type I interferon-IRF3-dependent manner. Memory CD8+ T cells became potent effector cells by sensing inflammation from monocytes independently of their cognate antigen. Like NK cells, they underwent rapid mobilization, upregulated intense and sustained effector functions during bacterial, viral, and parasitic infections, and contributed to innate responses and protection in vivo. Thus, inflammatory monocyte-derived IL-18 and IL-15 are critical to initiate memory CD8+ T and NK lymphocytes differentiation into antimicrobial effector cells.
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► Inflammatory Ly6C+ monocytes activate memory CD8+ T and NK lymphocytes ► Early reactivation of memory CD8+ T cells does not require cognate antigen ► Inflammatory monocytes provide the lymphocyte-activating cytokines IL-18 and IL-15 ► Memory CD8+ T lymphocytes contribute to host innate immune responses
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells ...(mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (T
reg
) cell development
1–4
. Within weeks of birth, a separate wave of T
reg
cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota
5–8
, yet the cell types responsible for the generation of peripheral T
reg
(pT
reg
) cells have not been identified. Here we describe the identification of a class of RORγt
+
antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I–TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pT
reg
cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pT
reg
generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pT
reg
differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt
+
group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pT
reg
generation, further implicating TC IV as the tolerogenic RORγt
+
antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Presence of TGFβ in the tumor microenvironment is one of the most relevant cancer immune-escape mechanisms. TGFβ is secreted in an inactive form, and its activation within the tumor may depend on ...different cell types and mechanisms than its production. Here we show in mouse melanoma and breast cancer models that regulatory T (Treg) cells expressing the β8 chain of αvβ8 integrin (Itgβ8) are the main cell type in the tumors that activates TGFβ, produced by the cancer cells and stored in the tumor micro-environment. Itgβ8 ablation in Treg cells impairs TGFβ signalling in intra-tumoral T lymphocytes but not in the tumor draining lymph nodes. Successively, the effector function of tumor infiltrating CD8
T lymphocytes strengthens, leading to efficient control of tumor growth. In cancer patients, anti-Itgβ8 antibody treatment elicits similar improved cytotoxic T cell activation. Thus, this study reveals that Treg cells work in concert with cancer cells to produce bioactive-TGFβ and to create an immunosuppressive micro-environment.
Regulatory T (Treg) cells play a pivotal role in suppressing self-harmful T cell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limit responses during ...inflammation is unclear. Here we show that effector Treg cells express high amounts of the integrin αvβ8, which enables them to activate latent transforming growth factor-β (TGF-β). Treg-cell-specific deletion of integrin αvβ8 did not result in a spontaneous inflammatory phenotype, suggesting that this pathway is not important in Treg-cell-mediated maintenance of immune homeostasis. However, Treg cells lacking expression of integrin αvβ8 were unable to suppress pathogenic T cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cells suppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activation of latent TGF-β in suppression of self-harmful T cell responses during active inflammation.
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•Human and mouse effector Treg cells express functional TGF-β-activating integrin αvβ8•Treg cell integrin αvβ8-mediated TGF-β activation is not needed for T cell homeostasis•Integrin αvβ8 expression by Treg cells suppresses active inflammation•Pathway could be targeted to promote Treg-cell-mediated suppression of inflammation
Regulatory T (Treg) cells suppress harmful T cell responses, but mechanisms mediating suppressive function during homeostasis versus inflammation are poorly defined. Travis and colleagues show that activation of the cytokine TGF-β by effector Treg cells, via expression of integrin αvβ8, is crucial for Treg-cell-mediated suppression of inflammatory T cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Bone loss associated with estrogen deficiency indicates a fundamental role of these hormones in skeletal growth and bone remodeling. In the last decades, growing recent evidence demonstrated that ...estrogens can also affect the immune compartment of the bone. In this review, we summarize the impacts of estrogens on bone immune cells and their consequences on bone homeostasis, metastasis settlement into the bone and tumor progression. We also addressed the role of an orphan nuclear receptor ERRalpha ("Estrogen-receptor Related Receptor alpha") on macrophages and T lymphocytes, and as an immunomodulator in bone metastases. Hence, this review links estrogens to bone immune cells in osteo-oncology.
SMAD4, a mediator of TGF-β signaling, plays an important role in T cells to prevent inflammatory bowel disease (IBD). However, the precise mechanisms underlying this control remain elusive. Using ...both genetic and epigenetic approaches, we revealed an unexpected mechanism by which SMAD4 prevents naive CD8+ T cells from becoming pathogenic for the gut. Prior to the engagement of the TGF-β receptor, SMAD4 restrains the epigenetic, transcriptional, and functional landscape of the TGF-β signature in naive CD8+ T cells. Mechanistically, prior to TGF-β signaling, SMAD4 binds to promoters and enhancers of several TGF-β target genes, and by regulating histone deacetylation, suppresses their expression. Consequently, regardless of a TGF-β signal, SMAD4 limits the expression of TGF-β negative feedback loop genes, such as Smad7 and Ski, and likely conditions CD8+ T cells for the immunoregulatory effects of TGF-β. In addition, SMAD4 ablation conferred naive CD8+ T cells with both a superior survival capacity, by enhancing their response to IL-7, as well as an enhanced capacity to be retained within the intestinal epithelium, by promoting the expression of Itgae, which encodes the integrin CD103. Accumulation, epithelial retention, and escape from TGF-β control elicited chronic microbiota-driven CD8+ T cell activation in the gut. Hence, in a TGF-β-independent manner, SMAD4 imprints a program that preconditions naive CD8+ T cell fate, preventing IBD.
Regulatory T (Treg) cells play a pivotal role in suppressing self-harmful T cell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limit responses during ...inflammation is unclear. Here we show that effector Treg cells express high amounts of the integrin alpha v beta 8, which enables them to activate latent transforming growth factor- beta (TGF- beta ). Treg-cell-specific deletion of integrin alpha v beta 8 did not result in a spontaneous inflammatory phenotype, suggesting that this pathway is not important in Treg-cell-mediated maintenance of immune homeostasis. However, Treg cells lacking expression of integrin alpha v beta 8 were unable to suppress pathogenic T cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cells suppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activation of latent TGF- beta in suppression of self-harmful T cell responses during active inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Transforming growth factor-β (TGF-β) is a major immunosuppressive cytokine that maintains immune homeostasis and prevents autoimmunity through its antiproliferative and anti-inflammatory properties ...in various immune cell types. We provide genetic, pharmacologic, and biochemical evidence that a critical target of TGF-β signaling in mouse and human natural killer (NK) cells is the serine and threonine kinase mTOR (mammalian target of rapamycin). Treatment of mouse or human NK cells with TGF-β in vitro blocked interleukin-15 (IL-15)-induced activation of mTOR. TGF-β and the mTOR inhibitor rapamycin both reduced the metabolic activity and proliferation of NK cells and reduced the abundances of various NK cell receptors and the cytotoxic activity of NK cells. In vivo, constitutive TGF-β signaling or depletion of mTOR arrested NK cell development, whereas deletion of the TGF-β receptor subunit TGF-βRII enhanced mTOR activity and the cytotoxic activity of the NK cells in response to IL-15. Suppression of TGF-β signaling in NK cells did not affect either NK cell development or homeostasis; however, it enhanced the ability of NK cells to limit metastases in two different tumor models in mice. Together, these results suggest that the kinase mTOR is a crucial signaling integrator of pro- and anti-inflammatory cytokines in NK cells. Moreover, we propose that boosting the metabolic activity of antitumor lymphocytes could be an effective strategy to promote immune-mediated tumor suppression.
The relationship between host organisms and their microbiota has co‐evolved towards an inter‐dependent network of mutualistic interactions. This interplay is particularly well studied in the ...gastrointestinal tract, where microbiota and host immune cells can modulate each other directly, as well as indirectly, through the production and release of chemical molecules and signals. In this review, we define the functional impact of transforming growth factor‐beta (TGF‐β) on this complex interplay, especially through its modulation of the activity of local regulatory T cells (Tregs), type 17 helper (Th17) cells, innate lymphoid cells (ILCs) and B cells.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Transforming growth factor-β (TGF-β) has been implicated in the control of differentiation and proliferation of multiple cell types. However, a role for TGF-β in the control of immune homeostasis is ...not fully understood because of its pleiotropic action. Here we report that complete ablation of the TGF-β signaling in T cells engendered aggressive early-onset, multiorgan, autoimmune-associated lesions with 100% mortality. Peripheral CD4
+ and CD8
+ T cells with TGF-β-receptor II (TGF-βRII) deficiency activated cytolytic and T helper 1 (Th1) differentiation program in a cell-intrinsic T cell receptor (TCR)-specific fashion. Furthermore, TGF-βRII deficiency blocked the development of canonical CD1d-restricted NKT cells. Instead, it facilitated generation of a highly pathogenic T cell subset exhibiting multiple hallmarks of NK cells and sharply elevated amounts of FasL, perforin, granzymes, and interferon-γ. Thus, TGF-β signaling in peripheral T cells is crucial in restraining TCR activation-dependent Th1, cytotoxic, and NK cell-like differentiation program which, when left unchecked, leads to rapidly progressing fatal autoimmunity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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