Absence Of CD103 Research Articles

Tumor-resident memory CD8+ T cells have a pivotal role in cancer immunity and immunotherapy.

Abstract CD8+ resident memory T (TRM) cells expressing the CD103 integrin frequently accumulate in human lung tumors and are associated with a favorable prognosis. However, the contribution of this T-cell subset to anti-tumor immunity and to the response to immune checkpoint blockade (ICB) immunotherapy has not been established. Using quantitative multiplex immunofluorescence staining on a cohort of non-small-cell lung cancer (NSCLC) patients treated with PD-1-targeted immunotherapy, we show that an increased density of CD103+CD8+ cells in tumors is associated with greatly improved outcome. CD103+CD8+ cells co-expressed CD49a and CD69, and display a molecular profile characterized by expression of PD-1 and CD39 exhaustion markers, and T-bet, AhR and phosphorylated-STAT-3 transcriptions factors, which confer them a Tc1/Tc17 profile. Moreover, CD103+CD8+ tumor TRM cells, but not CD103−CD8+ (non-TRM) tumor-infiltrating counterparts, demonstrate enhanced proliferation and cytotoxicity toward autologous cancer cells, and display oligoclonal expansion of specific TCRβ clonotypes. Human lung tumors are also infiltrated by CD103+CD4+ T cells likely suggesting a role for this resident population in orchestrating the antitumor T-cell response. Moreover, data obtained in pre-clinical mouse tumor models demonstrate that the absence of CD103 on CD8+ T cells impact the antitumor immune responses. These results explain why CD103+CD8+ tumor-reactive TRM cells are associated with better outcome in ICB-treated patients.

Specific Subset of Dendritic Cells Control the Priming of Mucosal Th17 Cells

Abstract Phagocytic mononuclear cells play an essential role in regulating gut immune homeostasis by sensing, internalizing microbial parts, and subsequently driving adaptive response in an antigen- and cytokine-dependent context. In a healthy host, physiological Th17 cells are predominantly generated in the gut, induced by local commensal microbiota. However, the precise subpopulation of antigen-presenting cells responsible for imprinting Th17 program in naïve CD4 T cells have not yet been definitively identified. Objective Mapping the functional subset of Th17-inducing dendritic cells (DCs) will uncover new targets for mucosal vaccine design. Methods & Results Using transgenic CD4 T cells specifically recognizing a gut-colonizing commensal bacterial antigen, we found that migratory DCs (CD11chiMHCIIhiZbtb46+) in the mesenteric lymph nodes are indispensable for the initial Th17 cell priming. Whereas the absence of CD103+ or CX3CR1+ DCs did not impact Th17 cell differentiation. Single cell RNA sequencing revealed that the migratory DCs are highly heterogeneous and consist of 8 clusters of transcriptionally specialized subsets. Interleukin-6, the Th17-polarizing cytokine, is expressed by a minor population of DCs with a type I interferon signature. Our results indicate that during homeostasis, Th17 cells activation in the mesenteric lymph nodes and later persistence in the small intestine may be controlled and sustained by different groups of antigen-presenting cells. The complexity and heterogeneity of mucosal DCs imply that other effector and regulatory T cell responses may be regulated by different DC subsets at this unique tissue environment.

March1-dependent modulation of donor MHC II on CD103+ dendritic cells mitigates alloimmunity

In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103+ DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103+ do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103+DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD103+DCs.

TGF\u03b2R signalling controls CD103+CD11b+ dendritic cell development in the intestine

CD103+CD11b+ dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFβR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103+CD11b+ DCs and a reciprocal increase in the CD103−CD11b+ dendritic cell subset. Transcriptional profiling identifies markers that define the CD103+CD11b+ DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103+CD11b+ DCs in CD11c-Cre.Tgfbr1fl/fl mice reflects defective differentiation from CD103−CD11b+ intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103+CD11b+ DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3+ regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFβR1-mediated signalling may explain the tissue-specific development of these unique DCs.

A pathogenic role for the integrin CD103 in experimental allergic airways disease.

The integrin CD103 is the α E chain of integrin α E β 7 that is important in the maintenance of intraepithelial lymphocytes and recruitment of T cells and dendritic cells (DC) to mucosal surfaces. The role of CD103 in intestinal immune homeostasis has been well described, however, its role in allergic airway inflammation is less well understood. In this study, we used an ovalbumin (OVA)‐induced, CD103‐knockout (KO) BALB/c mouse model of experimental allergic airways disease (EAAD) to investigate the role of CD103 in disease expression, CD4+ T‐cell activation and DC activation and function in airways and lymph nodes. We found reduced airways hyper‐responsiveness and eosinophil recruitment to airways after aerosol challenge of CD103 KO compared to wild‐type (WT) mice, although CD103 KO mice showed enhanced serum OVA‐specific IgE levels. Following aerosol challenge, total numbers of effector and regulatory CD4+ T‐cell subsets were significantly increased in the airways of WT but not CD103 KO mice, as well as a lack of DC recruitment into the airways in the absence of CD103. While total airway DC numbers, and their in vivo allergen capture activity, were essentially normal in steady‐state CD103 KO mice, migration of allergen‐laden airway DC to draining lymph nodes was disrupted in the absence of CD103 at 24 h after aerosol challenge. These data support a role for CD103 in the pathogenesis of EAAD in BALB/c mice through local control of CD4+ T cell and DC subset recruitment to, and migration from, the airway mucosa during induction of allergic inflammation.

Systemic sensitization with the protein allergen ovalbumin augments local sensitization in atopic dermatitis

Mouse models of atopic dermatitis based on epicutaneous sensitization have shed light on the role of epicutaneous allergen entry in the development of respiratory and gastrointestinal allergy. However, the contribution of non-cutaneous modes of sensitization to skin diseases has not been evaluated. We assessed if systemic ovalbumin administration, in conjunction with local sensitization, could prime for a robust inflammatory response. Furthermore, we attempted to elucidate important aspects of disease pathogenesis previously unaddressed in mouse models. Mice that underwent intraperitoneal ovalbumin sensitization prior to epicutaneous challenge demonstrated an acute (Th2-polarized) atopic dermatitis-like phenotype upon local challenge. The inflammatory response was strikingly more robust than in mice that underwent epicutaneous sensitization alone. The lesional infiltrate contained a dendritic cell population that corresponded phenotypically with inflammatory dendritic epidermal cells of significance in human disease. Finally, in accordance with observations in human atopic dermatitis, there was an increase in cluster of differentiation (CD) 103 (αE subunit)-expressing CD4+ T lymphocytes. However, the absence of CD103 on approximately 50% of infiltrating cells argues against a primary role for the αEβ7 integrin in tissue homing. In conclusion, we present a mouse model of atopic dermatitis that reveals novel insights into the pathogenesis of this complex disease.

Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism

Dendritic cells (DCs) in the intestinal lamina propria (LP) are composed of two CD103(+) subsets that differ in CD11b expression. We report here that Langerin is expressed by human LP DCs and that transgenic human langerin drives expression in CD103(+)CD11b(+) LP DCs in mice. This subset was ablated in huLangerin-DTA mice, resulting in reduced LP Th17 cells without affecting Th1 or T reg cells. Notably, cognate DC-T cell interactions were not required for Th17 development, as this response was intact in huLangerin-Cre I-Aβ(fl/fl) mice. In contrast, responses to intestinal infection or flagellin administration were unaffected by the absence of CD103(+)CD11b(+) DCs. huLangerin-DTA x BatF3(-/-) mice lacked both CD103(+) LP DC subsets, resulting in defective gut homing and fewer LP T reg cells. Despite these defects in LP DCs and resident T cells, we did not observe alterations of intestinal microbial communities. Thus, CD103(+) LP DC subsets control T cell homeostasis through both nonredundant and overlapping mechanisms.

Assessing the Role of CD103 in Immunity to an Intestinal Helminth Parasite

BackgroundIn the intestine, the integrin CD103 is expressed on a subset of T regulatory (Treg) cells and a population of dendritic cells (DCs) that produce retinoic acid and promote immune homeostasis. However, the role of CD103 during intestinal helminth infection has not been tested.Methodology/Principal FindingsWe demonstrate that CD103 is dispensable for the development of protective immunity to the helminth parasite Trichuris muris. While we observed an increase in the frequency of CD103+ DCs in the lamina propria (LP) following acute high-dose infection with Trichuris, lack of CD103 had no effect on the frequency of CD11c+ DCs in the LP or mesenteric lymph nodes (mLN). CD103-deficient (CD103−/−) mice develop a slightly increased and earlier T cell response but resolve infection with similar kinetics to control mice. Similarly, low-dose chronic infection of CD103−/− mice with Trichuris resulted in no significant difference in immunity or parasite burden. Absence of CD103 also had no effect on the frequency of CD4+CD25+Foxp3+ Treg cells in the mLN or LP.Conclusions/SignificanceThese results suggest that CD103 is dispensable for intestinal immunity during helminth infection. Furthermore, lack of CD103 had no effect on DC or Treg recruitment or retention within the large intestine.