Acute viral infection causes illness and death. In addition, an infection often results in increased susceptibility to a secondary infection, but the mechanisms behind this susceptibility are poorly understood. Since its initial identification as a marker for resident memory CD8+ T cells in barrier tissues, the function and regulation of CD103 integrin (encoded by ITGAE gene) have been extensively investigated. Nonetheless, the function and regulation of the resident CD103+CD8+ T cell response to acute viral infection remain unclear. Although TGFβ signaling is essential for CD103 expression, the precise molecular mechanism behind this regulation is elusive. Here, we reveal a TGFβ-SKI-Smad4 pathway that critically and specifically directs resident CD103+CD8+ T cell generation for protective immunity against primary and secondary viral infection. We found that resident CD103+CD8+ T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice. CD103 acts as a costimulation signal to produce an optimal antigenic CD8+ T cell response to acute viral infection. There is a reduction in resident CD103+CD8+ T cells following primary infection that results in increased susceptibility of the host to secondary infection. Intriguingly, CD103 expression inversely and specifically correlates with SKI proto-oncogene (SKI) expression but not R-Smad2/3 activation. Ectopic expression of SKI restricts CD103 expression in CD8+ T cells in vitro and in vivo to hamper viral clearance. Mechanistically, SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner. Our study therefore reveals that resident CD103+CD8+ T cells dictate protective immunity during primary and secondary infection. Interfering with SKI function may amplify the resident CD103+CD8+ T cell response to promote protective immunity.

The SKI proto-oncogene restrains the resident CD103 + CD8 + T cell response in viral clearance

Sequential immunotherapy: towards cures for autoimmunity

/pdf/pancreaticojejunostomy-conducive-to-biological-healing-in-3f9mj75y.pdf

Pancreaticojejunostomy Conducive to Biological Healing in Minimally Invasive Pancreaticoduodenectomy

Cancer is one of the most difficult diseases to be treated in the world. Immunotherapy has made great strides in cancer treatment in recent years, and several tumor immunotherapy drugs have been approved by the U.S. Food and Drug Administration. Currently, immunotherapy faces many challenges, such as lacking specificity, cytotoxicity, drug resistance, etc. Nanoparticles have the characteristics of small particle size and stable surface function, playing a miraculous effect in anti-tumor treatment. Nanocarriers such as polymeric micelles, liposomes, nanoemulsions, dendrimers, and inorganic nanoparticles have been widely used to overcome deficits in cancer treatments including toxicity, insufficient specificity, and low bioavailability. Although nanomedicine research is extensive, only a few nanomedicines are approved to be used. Either Bottlenecks or solutions of nanomedicine in immunotherapy need to be further explored to cope with challenges. In this review, a brief overview of several types of cancer immunotherapy approaches and their advantages and disadvantages will be provided. Then, the types of nanomedicines, drug delivery strategies, and the progress of applications are introduced. Finally, the application and prospect of nanomedicines in immunotherapy and Chimeric antigen receptor T-cell therapy (CAR-T) are highlighted and summarized to address the problems of immunotherapy the overall goal of this article is to provide insights into the potential use of nanomedicines and to improve the efficacy and safety of immunotherapy.

Activation of cancer immunotherapy by nanomedicine

Introduction The ability of dendritic cells (DCs) to initiate an immune response or induce immune tolerance depends on their maturation status. Dendritic-cell-associated C-type lectin 1 (Dectin-1) plays a key role in the differentiation, activation, and maturation of DCs. Therefore, we hypothesized that inhibition of Dectin-1 could prevent DC maturation and induce immune tolerance of transplanted organs. Methods DCs were transduced with a recombinant lentiviral vector to inhibit Dectin-1 and then were injected into a murine recipient before islet transplantation. C57BL/6 mice (H-2b) were treated with lentiviral vector-Dectin-1-RNAi-DC (DC-Dectin-1-RNAi group), lentiviral vector-GFP DCs (DC-GFP group), and PBS (control group). Pancreatic islet transplantation was performed and graft survival was recorded. The proportions of regulatory T cells, Th1 cells, and Th17 cells in the spleen and draining lymph nodes, and serum levels of interleukin (IL)-10, IL-17, and interferon (INF)-γ were measured. Results The inhibition of Dectin-1 resulted in low expression of MHC-II and costimulatory molecules in DCs. Murine recipients treated with DC-Dectin-1-RNAi had longer islet allograft survival time, a reduction in the levels of Th1 and Th17 cells and secreted cytokines, and an increase of Treg cells. Conclusion The inhibition of Dectin-1 by recombinant lentiviral vector Dectin-1-RNAi inhibits the maturation and activation of DCs, affects the differentiation of T cell subsets, and prolongs allograft survival.

/pdf/inhibition-of-dectin-1-on-dendritic-cells-prevents-5feh2e1nhm.pdf

Inhibition of Dectin-1 on Dendritic Cells Prevents Maturation and Prolongs Murine Islet Allograft Survival.

Effect of six-stitch pancreaticojejunostomy on pancreatic fistula: A propensity score-matched comparative cohort study

CD103 mediates T-cell infiltration and organ allograft rejection, and depletion of CD103-expressing cells is a promising therapeutic strategy for allograft intolerance. Recently, we verified that M290-MC-MMAF, an anti-CD103 antibody-drug conjugate, potently eliminates CD103-positive cells in vivo, with high specificity and minimal toxicity. However, the contribution of M290-MC-MMAF to blocking the CD103/E-cadherin pathway involved in transplant rejection remains unclear. Herein, we examined the impact of systemic administration of M290-MC-MMAF on allografts in an islet transplantation model. M290-MC-MMAF treatment maintained the long-term survival of islet allografts (>60 days) compared to mock injection or unconjugated M290 antibody treatment (<18 days). The change was associated with a decrease in CD103+CD8+ effector T cells and an increase in CD4+CD25+ regulatory T cells. CD103+CD8+ effector T-cell transfer or CD4+CD25+ regulatory T-cell depletion resulted in a rapid loss of allografts in long-surviving islet hosts. Moreover, M290-MC-MMAF treatment reduced IL-4, IL-6, and TNF-α expression levels and increased IL-10 expression in the grafts, which presented an immunosuppressive cytokine profile. In conclusion, targeting CD103 with M290-MC-MMAF induced immunosuppression and prolonged the survival of pancreatic islet allografts in mice, indicating the potential clinical value of M290-MC-MMAF in therapeutic interventions for allograft rejection.

/pdf/an-anti-cd103-antibody-drug-conjugate-prolongs-the-survival-1gbh6chssj.pdf

An anti-CD103 antibody-drug conjugate prolongs the survival of pancreatic islet allografts in mice

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Effect of six-stitch pancreaticojejunostomy on pancreatic fistula: A propensity score-matched comparative cohort study

An anti-CD103 antibody-drug conjugate prolongs the survival of pancreatic islet allografts in mice