Feedback Interactions between Dendritic Cells and CD8+ T Cells during the Development of Type-1 Immunity

CD8+ T cell responses are crucial for immunity against intracellular infections and can mediate tumor regression. While CD8+ T cells are widely recognized as cytolytic effector cells (cytolytic T cells; CTLs), little is known about their immunoregulatory functions and their impact on dendritic cells (DCs). A similar area of controversy is the role of DC in regulating the induction of CD8+ T cell effector functions and CD8+ T cell memory. This dissertation addresses the impact of bidirectional communication between DCs and CD8+ T cells, during different phases of the immune response, upon the functions of both these cell types. In order to reconcile the apparently contrasting notions that CD8+ T cells perform both "suppressor" and "helper" functions, I compared the DC-modulating activity of CD8+ T cells at different stages of activation. I observed that DC-killing and DC-activating (and protective) functions are exerted sequentially by activated CD8+ T cells. In contrast to the effector cells that kill DCs in a granzyme B/perforin-dependent manner, memory CD8+ T cells promote IL-12 production in DCs and support CD4+ and CD8+ T cell responses. Moreover, memory CD8+ T cells instruct DC to over-express granzyme B inhibitor PI-9, protecting them from elimination by CTLs. I observed that the inclusion of "heterologous" CD8+ T cell epitopes in cancer vaccines, promoting the interaction of vaccine-bearing DCs with large numbers of tumor-unrelated CD8+ T cells, strongly enhances the immunologic and therapeutic activity of vaccination against established tumors that are resistant to standard vaccines.Since the character of the vaccination-induced CD8+ T cells is important for the efficacy of cancer immunotherapy, I have analyzed the role of DCs in influencing the cytolytic function and peripheral tissue-homing ability of CD8+ T cells. I observed that short-term-activated "inflammatory-type" DCs, capable of producing high levels of IL-12 and other pro-inflammatory cytokines, support induction of cytotoxic function and a switch from lymphoid to peripheral chemokine receptors in CD8+ T cells. In contrast, "exhausted" DCs matured for extended periods of time or matured under the influence of the mediators of chronic inflammation, favor CD8+ T cell expansion alone without acquisition of effector functions.Collectively, the findings presented in this dissertation broaden our understanding of the feedback circuitry between CD8+ T cells and DCs and will help us to design improved vaccines against cancer and chronic infections

Interactive teaching and repeat exposure maximize medical student satisfaction but do not promote long-term retention of dermatologic knowledge

Background: Instructional methods for teaching medical students to recognize common skin lesions vary widely. There is little published data comparing various teaching methods and their impact on medical student retention of dermatologic knowledge. Methods: Our prospective cohort study analyzed how teaching methods (interactive teaching versus. traditional didactic teaching versus. self-guided review alone) impacted second year medical students' ability to recognize common skin lesions one year after initial exposure to the material. Our study also looked at student satisfaction with different teaching methods. Results: There was no significant difference in long-term retention of knowledge between different teaching methods. However, students preferred the interactive format over the traditional didactic format. Spaced review is important for long-term retention, but an in-class review session two months after content was initially taught provided no added benefit over spaced self-review alone. Conclusions: Medical students are able to maintain long-term retention of dermatologic knowledge irrespective of in-class teaching method. Repeat exposure to material is important but self-review of dermatology alone is sufficient for long-term retention. Dermatology course directors should incorporate interactive teaching into medical school curricula to increase learner satisfaction

BSAVA Formulary: Your questions answered

A new edition of the BSAVA Small Animal Formulary has been published. Ian Ramsey explains what is in and what is out of this new version

Signal regulatory protein alpha (SIRPα) regulates the homeostasis of CD103⁺CD11b⁺ DCs in the intestinal lamina propria

Signal regulatory protein alpha (SIRP alpha/CD172a) is a conserved transmembrane protein thought to play an inhibitory role in immune function by binding the ubiquitous ligand CD47. SIRP alpha expression has been used to identify dendritic cell subsets across species and here we examined its expression and function on intestinal DCs in mice. Normal mucosa contains four subsets of DCs based on their expression of CD103 and CD11b and three of these express SIRP alpha. However, loss of SIRP alpha signaling in mice leads to a selective reduction in the CD103(+)CD11b(+) subset of DCs in the small intestine, colon, and amongmigratory DCs in the mesenteric lymph node. In parallel, these mice have reduced numbers of T(H)17 cells in steady-state intestinal mucosa, and a defective T(H)17 response to Citrobacter infection. Identical results were obtained in CD47KO mice. DC precursors from SIRP alpha mutant mice had an enhanced ability to generate CD103(+)CD11b(+) DCs in vivo, but CD103(+)CD11b(+) DCs from mutant mice were more prone to die by apoptosis. These data show a previously unappreciated and crucial role for SIRP alpha in the homeostasis of CD103(+)CD11b(+) DCs in the intestine, as well as providing further evidence that this subset of DCs is critical for the development of mucosal T(H)17 responses

Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T cell response in low-grade gliomas

BACKGROUND. Long-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy. METHODS. We conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor. RESULTS. A total of 17 eligible patients were enrolled — 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident–like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination. CONCLUSION. The regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies

Compartment-specific immunity in the human gut: Properties and functions of dendritic cells in the colon versus the ileum

© 2015 The Authors. Published by BMJ. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: http://dx.doi.org/10.1136/gutjnl-2014-307916Objective Dendritic cells (DC) mediate intestinal immune tolerance. Despite striking differences between the colon and the ileum both in function and bacterial load, few studies distinguish between properties of immune cells in these compartments. Furthermore, information of gut DC in humans is scarce. We aimed to characterise human colonic versus ileal DC. Design Human DC from paired colonic and ileal samples were characterised by flow cytometry, electron microscopy or used to stimulate T cell responses in a mixed leucocyte reaction. Results A lower proportion of colonic DC produced pro-inflammatory cytokines (tumour necrosis factor-a and interleukin (IL)-1ß) compared with their ileal counterparts and exhibited an enhanced ability to generate CD4+FoxP3+IL-10+ (regulatory) T cells. There were enhanced proportions of CD103+Sirpa- DC in the colon, with increased proportions of CD103+Sirpa+ DC in the ileum. A greater proportion of colonic DC subsets analysed expressed the lymph-node-homing marker CCR7, alongside enhanced endocytic capacity, which was most striking in CD103+Sirpa+ DC. Expression of the inhibitory receptor ILT3 was enhanced on colonic DC. Interestingly, endocytic capacity was associated with CD103+ DC, in particular CD103+Sirpa+ DC. However, expression of ILT3 was associated with CD103- DC. Colonic and ileal DC differentially expressed skin-homing marker CCR4 and small-bowel-homing marker CCR9, respectively, and this corresponded to their ability to imprint these homing markers on T cells. Conclusions The regulatory properties of colonic DC may represent an evolutionary adaptation to the greater bacterial load in the colon. The colon and the ileum should be regarded as separate entities, each comprising DC with distinct roles in mucosal immunity and imprinting.This research was funded by St. Mark's Foundation (Harrow, UK), The Biotechnology and Biological Sciences Research Council (BBSRC; BB/J004529/1) and The National Institutes of Health (NIH; US) including The National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK; T32-DK07632 and P01-DK072084) and The National Institute of Allergy and Infectious Disease (NIH/NIAID; R21-AI094033). We also gratefully acknowledge funding support from The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Centre at The Johns Hopkins Hospital, Baltimore, US.Published versio

Human dermal CD14⁺ cells are a transient population of monocyte-derived macrophages.

Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141(hi)XCR1⁺ CLEC9A⁺ DCs and CD1c⁺ DCs are murine CD103⁺ DCs and CD64⁻ CD11b⁺ DCs. In addition, human tissues also contain CD14⁺ cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14⁺ cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of <6 days. The decline and reconstitution kinetics of human blood CD14⁺ monocytes and dermal CD14⁺ cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14⁺ cells are CD11b⁺ CD64⁺ monocyte-derived macrophages. Human and mouse monocytes and macrophages were defined by highly conserved gene transcripts, which were distinct from DCs. The demonstration of monocyte-derived macrophages in the steady state in human tissue supports a conserved organization of human and mouse mononuclear phagocyte system