“The disease in a patient often sets standards for the quality of new information and principles that scientist still need to discover.”
Ralph Steinman
Our research program focus on understanding principles of healthy human immune response and its alteration in disease in patients. We aim to harness these principles we discover for the development of novel immune-based treatments for some of the most challenging human diseases.
Dendritic cells are a group of cells with a unique capacity to sense and respond to the environment and induce adaptive and long-term memory immunity against specific antigens. We’ve been studying basic principals by which human dendritic cells subsets exert their function, with the ultimate goal of harnessing our understanding of the innate immune system to develop novel therapies against cancer and inflammatory diseases. Our laboratory has also made pioneering discoveries in the identifications of novel dendritic cell types, and have been working to identify the dendritic cell-derived factors that contribute to the activation of T cells and other immune cells.
Human Dendritic Cell Biology
Our laboratory is focused on understanding principles by which Myeloid cells control immunity including:
1) Initiation of immune responses: We pursued our initial observations that human epidermal DCs, called Langerhans Cells, are effective at priming CTL responses (Immunity 2008). We demonstrated that LCs present IL-15 at the immunological synapse to promote CD8+ T cell immunity (Blood 2012; Sci. Immunol. 2018). In addition, we showed that human LCs share a Class I–mediated antigen processing and cross-presentation transcriptional module with XCR1+CD103+ DCs, rather than LCs, in mouse (JEM 2015). Our study highlighted the fact that, although human and mouse LCs share the same anatomical location and some markers, functionally they may not be evolutionary conserved, supporting the idea that human LCs are a relevant therapeutic target.
2) Mechanisms for tolerance induction by myeloid cells: We demonstrated that dermal CD14+ DCs actively inhibit cytotoxic T cell (CTL) responses through the production of IL-10 and transforming growth factor-β (Blood 2012). In addition, we found, that the expression of the immunoglobulin-like transcript (ILT) receptors ILT2 and ILT4 on dermal CD14+ DCs attenuate cellular immune responses. ILTs bind MHC Class I molecules and interfere sterically with CD8 co-receptor binding, which impairs interaction of T cell receptors with the peptide–MHC complex to inhibit CD8+ T cell priming (PNAS 2012). This finding has important clinical implications, as ILT-antagonists are currently being evaluated as anti-cancer therapies.
3) Mechanisms related to the resolution of an immune response. We found that DC-intrinsic IL-15 induced the expression of a specific isoform of a human cytokine Interleukin 32 (IL-32), which, in a feedback loop, inhibits IL15-mediated NK cell cytolytic capacity by reducing STAT5 phosphorylation (JI 2017).
4) Identification and functional heterogeneity of novel DC subsets. Our lab identified a novel subset of CD141+ DCs in human skin (LC2013 meeting, JEM 2015). In addition, we discovered a terminally differentiated subset of CD1c+ cells expressing CD5 in skin, blood and lymph nodes. We published that CD5+ DCs are more potent activators of CD8+ and helper T cells compared to CD5- DCs. CD5+ DCs are now recognized by the research community as a subset of IRF4+ DCs.
Enhancing anti-tumor immunity via Dendritic cells
As the most potent antigen presenting cells, dendritic cells play a key role in inducing tumor-specific cytotoxic and helper T cells. We aim to understand at the cellular and molecular levels how dendritic cells with their subsets, contribute to tumor homeostasis, tumor immunity, and tumor response to existing immunotherapies. Using human cells and mouse models we study the mechanisms that drive potent anti-tumor immunity and ones that inhibits such critical processes within the tumor microenvironment.
Our goal is to integrate knowledge of human dendritic cell biology and targeting to develop novel effective therapeutic vaccines that mobilize dendritic cells, a critical component of the mammalian immune system.
DC subsets in autoinflammatory skin diseases
Understanding how human DC subsets function and engage their unique co-stimulatory repertoire for eliciting effective immunity – is an important objective for dissecting inflammation-based disease pathologies, and for developing novel therapeutic approaches to these conditions. Our integrated research program aim to establish mechanisms by which specific DC subsets facilitates inflammatory immune responses and early events leading to skin inflammation and T cell activation. In addition, we pursue translational component to define differences in the expression programs of DCs in patients with autoimmune skin disease, and examine how these classical DCs interact and activate autoreactive T cells in patients. Current therapies for this disease are non- specific, short lived, and associated with serious side effects including opportunistic infections and cancer. Our overall goal is to establish principle for the specific attenuation of auto-inflammation via dendritic cells.
Support Our Science
Some of the greatest discoveries in biomedical research came through direct donations from generous individuals. Would you like to collaborate in our fight against cancer and restrain autoimmunity? Your gift will directly support novel approaches to understand and harness our immune system to fight these diseases. please contact the Washington University in St. Louis University Advancement. Be sure to specifically assign the donation to the Eynav Klechevsky Lab at the school of Medicine.