Breaking self-tolerance during autoimmunity and cancer immunity: Myeloid cells and type I IFN response regulation

Tarbell, Kristin V.; Egen, Jackson G.

doi:10.1002/jlb.3mir1017-400r

Cited by 10 publications

(6 citation statements)

References 157 publications

(182 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As noted above, TYK2 P can function to limit IFN I signaling. IFN I signaling is increased in a subset of SLE subjects and IFN I blockade has provided partial benefit in some patients (61–63). Thus, the potential protective impact of Tyk2 P may be most relevant in lupus models that are driven or accelerated by an altered IFN I program.…”

Section: Discussionmentioning

confidence: 99%

The TYK2-P1104A Autoimmune Protective Variant Limits Coordinate Signals Required to Generate Specialized T Cell Subsets

Gorman¹,

Hundhausen²,

Kinsman³

et al. 2019

Front. Immunol.

View full text Add to dashboard Cite

TYK2 is a JAK family member that functions downstream of multiple cytokine receptors. Genome wide association studies have linked a SNP (rs34536443) within TYK2 encoding a Proline to Alanine substitution at amino acid 1104, to protection from multiple autoimmune diseases including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). The protective role of this SNP in autoimmune pathogenesis, however, remains incompletely understood. Here we found that T follicular helper (Tfh) cells, switched memory B cells, and IFNAR signaling were decreased in healthy individuals that expressed the protective variant TYK2A1104 (TYK2P). To study this variant in vivo, we developed a knock-in murine model of this allele. Murine Tyk2P expressing T cells homozygous for the protective allele, but not cells heterozygous for this change, manifest decreased IL-12 receptor signaling, important for Tfh lineage commitment. Further, homozygous Tyk2P T cells exhibited diminished in vitro Th1 skewing. Surprisingly, despite these signaling changes, in vivo formation of Tfh and GC B cells was unaffected in two models of T cell dependent immune responses and in two alternative SLE models. TYK2 is also activated downstream of IL-23 receptor engagement. Here, we found that Tyk2P expressing T cells had reduced IL-23 dependent signaling as well as a diminished ability to skew toward Th17 in vitro. Consistent with these findings, homozygous, but not heterozygous, Tyk2P mice were fully protected in a murine model of MS. Homozygous Tyk2P mice had fewer infiltrating CD4+ T cells within the CNS. Most strikingly, homozygous mice had a decreased proportion of IL-17+/IFNγ+, double positive, pathogenic CD4+ T cells in both the draining lymph nodes (LN) and CNS. Thus, in an autoimmune model, such as EAE, impacted by both altered Th1 and Th17 signaling, the Tyk2P allele can effectively shield animals from disease. Taken together, our findings suggest that TYK2P diminishes IL-12, IL-23, and IFN I signaling and that its protective effect is most likely manifest in the setting of autoimmune triggers that concurrently dysregulate at least two of these important signaling cascades.

show abstract

Section: Discussionmentioning

confidence: 99%

The TYK2-P1104A Autoimmune Protective Variant Limits Coordinate Signals Required to Generate Specialized T Cell Subsets

Gorman¹,

Hundhausen²,

Kinsman³

et al. 2019

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Cancer immunotherapy can produce excellent prognosis and prolong the survival of patients through triggering antitumor immune responses . However, current immunotherapy strategies get a relatively low response rate, − largely because there is a lack of effective strategies to break the tumoral immune tolerance for inducing antitumor immune responses. − …”

Section: Introductionmentioning

confidence: 99%

Cationic Liposome/DNA Complexes Mediate Antitumor Immunotherapy by Promoting Immunogenic Tumor Cell Death and Dendritic Cell Activation

Cong

Tian

Liu

et al. 2020

ACS Appl. Mater. Interfaces

View full text Add to dashboard Cite

Immunotherapy has been successfully used in the treatment of multiple malignancies, but clinical studies revealed low response rates. Thus, the development of new effective immunotherapeutic modalities is urgently needed. Successfully inducing tumor cell death with enhanced antigenicity is important for the expansion and differentiation of tumor-specific CD8 + cytotoxic T lymphocytes. Cationic liposome/DNA complexes (CLN/DNA), which usually have obvious cytotoxic effects, may improve the antitumor immunity through enhancing the immunogenicity of dying tumor cells. Herein, we report that a plasmid DNA-encapsulated cationic lipid nanoparticle formulated with cholesterol, DOTAP, and DSPE-mPEG 2000 significantly increases the tumor cell death with high antigenicity in vitro. Furthermore, the cationic liposome/DNA complex (CLN/DNA) treatment promotes the activation of dendritic cells (DCs). We also find that the intratumorally injected CLN/DNA successfully promoted the activation of DCs in the tumor-draining lymph node. Importantly, both local tumor growth and distant tumor formation were significantly inhibited by T cell-dependent antitumor immune responses after intratumoral injection of CLN/DNA. This study presents a simple and effective strategy for improving the cancer immunotherapy.

show abstract

“…However, where and how naïve cancer cell-specific CD4 T cells get activated in a tumor setting is less clear. Lessons learnt on the importance of MHC class II-restricted CD4 T cell responses in autoimmune pathogenesis may shed light on this question in anti-tumor responses as well, since the anti-tumor response is essentially a self-specific response (114). The highest genetic risk for autoimmunity is conferred by HLA class II genes, with odds ratios >6, suggesting that CD4 T cell responses are necessary for immunity against self.…”

Section: Introductionmentioning

confidence: 99%

Beyond cDC1: Emerging Roles of DC Crosstalk in Cancer Immunity

2019

Self Cite

View full text Add to dashboard Cite

Dendritic cells (DCs) efficiently process and present antigens to T cells, and by integrating environmental signals, link innate and adaptive immunity. DCs also control the balance between tolerance and immunity, and are required for T-cell mediated anti-tumor immunity. One subset of classical DCs, cDC1, are particularly important for eliciting CD8 T cells that can kill tumor cells. cDC1s are superior in antigen cross-presentation, a process of presenting exogenous antigens on MHC class I to activate CD8 + T cells. Tumor-associated cDC1s can transport tumor antigen to the draining lymph node and cross-present tumor antigens, resulting in priming and activation of cytotoxic T cells. Although cross-presenting cDC1s are critical for eliciting anti-tumor T cell responses, the role and importance of other DC subsets in anti-tumor immunity is not as well-characterized. Recent literature in other contexts suggests that critical crosstalk between DC subsets can significantly alter biological outcomes, and these DC interactions likely also contribute significantly to tumor-specific immune responses. Therefore, antigen presentation by cDC1s may be necessary but not sufficient for maximal immune responses against cancer. Here, we discuss recent advances in the understanding of DC subset interactions to maximize anti-tumor immunity, and propose that such interactions should be considered for the development of better DC-targeted immunotherapies.

show abstract

Breaking self-tolerance during autoimmunity and cancer immunity: Myeloid cells and type I IFN response regulation

Cited by 10 publications

References 157 publications

The TYK2-P1104A Autoimmune Protective Variant Limits Coordinate Signals Required to Generate Specialized T Cell Subsets

The TYK2-P1104A Autoimmune Protective Variant Limits Coordinate Signals Required to Generate Specialized T Cell Subsets

Cationic Liposome/DNA Complexes Mediate Antitumor Immunotherapy by Promoting Immunogenic Tumor Cell Death and Dendritic Cell Activation

Beyond cDC1: Emerging Roles of DC Crosstalk in Cancer Immunity

Contact Info

Product

Resources

About