ICOS+ Tregs: A Functional Subset of Tregs in Immune Diseases

Li, Dan Yang; Xiong, Xian Zhi

doi:10.3389/fimmu.2020.02104

Cited by 98 publications

(95 citation statements)

References 149 publications

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“…CTLA-4 has been shown to be indispensable in Treg-mediated immunosuppression, as CTLA-4 − Treg cells were unable to maintain self-tolerance and immune homeostasis, and Treg-specific CTLA-4 deactivation promoted anti-tumor immunity [ 19 ]. Moreover, GITR and ICOS molecules maintain Treg homeostasis, survival, and immunosuppressive functions [ 67 , 68 , 69 ]. Thus, we suppose that the immunosuppressive potential of subpopulations 1 and 2 was high, whereas the low CTLA-4 expression in subpopulations 3 and 4 implied limited immunosuppressive potential.…”

Section: Discussionmentioning

confidence: 99%

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CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

Vackova

Poláková

Johari

et al. 2021

Cancers

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Cluster of differentiation (CD) 80 is mainly expressed in immune cells but can also be found in several types of cancer cells. This molecule may either activate or inhibit immune reactions. Here, we determined the immunosuppressive role of CD80 in the tumor microenvironment by CRISPR/Cas9-mediated deactivation of the corresponding gene in the mouse oncogenic TC-1 cell line. The tumor cells with deactivated CD80 (TC-1/dCD80-1) were more immunogenic than parental cells and induced tumors that gained sensitivity to cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade, as compared with the TC-1 cells. In vivo depletion experiments showed that the deactivation of CD80 switched the pro-tumorigenic effect of macrophages observed in TC-1-induced tumors into an anti-tumorigenic effect in TC-1/dCD80-1 tumors and induced the pro-tumorigenic activity of CD4+ cells. Moreover, the frequency of lymphoid and myeloid cells and the CTLA-4 expression by T helper (Th)17 cells were increased in TC-1/dCD80-1- compared with that in the TC-1-induced tumors. CTLA-4 blockade downregulated the frequencies of most immune cell types and upregulated the frequency of M2 macrophages in the TC-1 tumors, while it increased the frequency of lymphoid cells in TC-1/dCD80-1-induced tumors. Furthermore, the anti-CTLA-4 therapy enhanced the frequency of CD8+ T cells as well as CD4+ T cells, especially for a Th1 subset. Regulatory T cells (Treg) formed the most abundant CD4+ T cell subset in untreated tumors. The anti-CTLA-4 treatment downregulated the frequency of Treg cells with limited immunosuppressive potential in the TC-1 tumors, whereas it enriched this type of Treg cells and decreased the Treg cells with high immunosuppressive potential in TC-1/dCD80-1-induced tumors. The immunosuppressive role of tumor-cell-expressed CD80 should be considered in research into biomarkers for the prediction of cancer patients’ sensitivity to immune checkpoint inhibitors and for the development of a tumor-cell-specific CD80 blockade.

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Section: Discussionmentioning

confidence: 99%

“…As previously noted, VEGF occurs in TC-1-induced tumors [ 71 ]. However, the ICOS − Treg subset has been defined as “death prone” [ 67 , 68 ]. Therefore, we presume that the immunosuppressive potential of subpopulation 4 was markedly limited.…”

Section: Discussionmentioning

confidence: 99%

CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

Vackova

Poláková

Johari

et al. 2021

Cancers

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“…It is known that ICOS deficiency can cause Foxp3 instability due to significant methylation of Foxp3 CNS2, resulting in a reduced number of FOXP3 + Tregs. In addition, ICOS signaling can promote the proliferation and survival of Tregs (42)(43)(44). On the other hand, the LATY136F mice do not have Treg cells (18) or have abnormal Treg cells that have much reduced Foxp3 expression (45).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Differentiation of T Follicular Helper Cells in LATY136F Mutant Mice

2021

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Mice with a mutation at the LAT-PLCγ1 binding site (Y136) have a defect in thymocyte development due to dampened TCR signaling. CD4+ T cells that do reach the periphery are hyper-activated and skewed to Th2. Over time, these mice develop an autoimmune-like syndrome, characterize by overproduction of Th2 cytokines, T cell infiltration into various organs, and B cell activation, isotype switching, and autoantibody production. In this study, we examined IL4 production by CD4+ T cells in the LATY136F mice using the KN2 reporter mice, in which human CD2 expression marks T cells that are actively producing IL4 protein. We showed that these mice had spontaneous Tfh differentiation. Despite the fact that the majority of CD4+ T cells were skewed to Th2 and were GATA3+, only a small subset of them were actively secreting IL4. These T cells were Tfh cells that expressed BCL6 and were localized to B cell-rich germinal centers within the spleen. Interestingly, these Tfh cells expressed high levels of both BCL6 and GATA3. By using LAT conditional knockout mice that inducibly express only the LATY136F allele, we further showed that Tfh cell differentiation was likely the result of defective LAT-PLCγ1 signaling in the periphery. In addition, B cells were required for spontaneous development of Tfh cells and uncontrolled T cell expansion in these mice. Together, these results indicated a novel role for tonic LAT-PLCγ1 signaling in modulating Tfh cell differentiation during development of autoimmune syndrome.

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“…Here we observed that the sub-population of Tregs in the skin that expresses the highest levels of α v β 3 was also highly positive for activation markers CD44 and ICOS, indicating that these cells are among the most highly activated Tregs present in the skin. As elevated ICOS expression distinguishes Tregs with high suppressive function ( 43 , 44 ), this provides evidence that α v β 3 serves as an additional adhesion molecule marker of highly-suppressive Tregs in inflamed skin. Notably, as the α v integrin was also critical for Treg migration at the peak of the CS response, this is consistent with this adhesion molecule facilitating migration of highly-functional Tregs throughout the inflamed skin.…”

Section: Discussionmentioning

confidence: 81%

“…Here we show that this pathway is also critical to migration of Tregs after they have crossed the endothelial barrier, not only in inflamed skin, but for the low proportion of migratory Tregs in non-inflamed skin. As the PI3K p110δ pathway acts downstream of the TCR and co-stimulatory molecules such as ICOS and CD28, this suggests that Tregs affected by inhibition of this pathway are responding to their cognate antigen via the TCR ( 39 , 44 ). Studies in which mature Tregs were rendered deficient in the TCR have demonstrated that Tregs require continuous stimulation via the TCR to maintain suppressor function and a transcriptional profile typical of mature, effector Tregs ( 45 , 46 ).…”

Section: Discussionmentioning

confidence: 99%

Dynamic Regulation of the Molecular Mechanisms of Regulatory T Cell Migration in Inflamed Skin

et al. 2021

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The presence of regulatory T cells (Tregs) in skin is important in controlling inflammatory responses in this peripheral tissue. Uninflamed skin contains a population of relatively immotile Tregs often located in clusters around hair follicles. Inflammation induces a significant increase both in the abundance of Tregs within the dermis, and in the proportion of Tregs that are highly migratory. The molecular mechanisms underpinning Treg migration in the dermis are unclear. In this study we used multiphoton intravital microscopy to examine the role of RGD-binding integrins and signalling through phosphoinositide 3-kinase P110δ (PI3K p110δ) in intradermal Treg migration in resting and inflamed skin. We found that inflammation induced Treg migration was dependent on RGD-binding integrins in a context-dependent manner. αv integrin was important for Treg migration 24 hours after induction of inflammation, but contributed to Treg retention at 48 hours, while β1 integrin played a role in Treg retention at the later time point but not during the peak of inflammation. In contrast, inhibition of signalling through PI3K p110δ reduced Treg migration throughout the entire inflammatory response, and also in the absence of inflammation. Together these observations demonstrate that the molecular mechanisms controlling intradermal Treg migration vary markedly according to the phase of the inflammatory response.

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ICOS+ Tregs: A Functional Subset of Tregs in Immune Diseases

Cited by 98 publications

References 149 publications

CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

Spontaneous Differentiation of T Follicular Helper Cells in LATY136F Mutant Mice

Dynamic Regulation of the Molecular Mechanisms of Regulatory T Cell Migration in Inflamed Skin

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