Comprehensive analysis of antigen-specific T cell repertoires in human blood
We have developed a novel assay which permits a comprehensive analysis of antigen-specific T cell repertoires in human blood (EpiMax). By using EpiMax together with other immunomonitoring tools, his lab has analyzed antigen-specific T cell subsets in patients with different diseases, and published findings including that 1) Patients with metastatic melanoma display tumor antigen-specific IL-10-producing regulatory T cells in blood. 2) Vaccinations with dendritic cells loaded with killed tumor cells induce a broad repertoire of tumor-antigen-specific CD8+ and CD4+ T cells in patients with metastatic melanoma. 3) Type 1 diabetes children and type 1 diabetes adults display distinct sets of islet antigen-specific CD4+ T cells.
Identification of developmental pathways of human T follicular helper (TFH) cells
Our lab has discovered multiple mechanisms that promote the differentiation of TFH cells in humans. They initially demonstrated that IL-12 induces human naïve CD4+ T cells to become IL-21+ TFH-like cells. Later, they have shown that children deficient of IL-12 receptor (beta 1 chain) show decreased circulating TFH cells and memory B cells in blood, and an altered formation of germinal centers in lymph nodes, indicating the importance of signals mediated via IL-12 receptor (thus IL-12 and IL-23) for optimal TFH response in vivo in humans. His recent study further identified that TGF-beta acts together with IL-12 and IL-23 to drive the differentiation of human naïve CD4+ T cells towards the TFH lineage. Interestingly, this pathway is shared with TH17 cell differentiation in humans. Given that both TFH and TH17 cell responses are often excessive in autoimmune disease patients, this pathway is likely involved in the co-development of the two T cell lineages in these diseases. His most recent study demonstrated that signals through Ox40 also promote the differentiation of TFH cells in humans, and provided evidence that the OX40-Ox40 ligand axis is involved in the generation of aberrant TFH response in systemic lupus erythematosus patients.
Phenotypic and functional characterization of human dendritic cell subsets
Our lab has shown that human skin dendritic cell subsets are functionally distinct and play distinct roles in the generation of immune responses. These studies also provided insights into the designs of dendritic cell-based immunotherapies for various diseases.
Human TFH cell subsets and their roles in diseases/vaccinations
Our lab has shown that CXCR5+ memory CD4+ T cells in human blood likely represent the circulating memory compartment of TFH cells. They further demonstrated that these circulating TFH cells (cTFH cells) are composed of three major subsets which share properties with TH1, TH2, and TH17 cells, and these subsets display different abilities to help B cells. They also provided evidence that the alteration in the composition of these subsets is associated with the pathogenesis of human autoimmune diseases. These findings were largely confirmed by studies performed by other laboratories and in many human autoimmune diseases. By using human tonsil samples, his lab has also demonstrated that TFH cells within germinal centers and TFH-lineage cells outside germinal centers display distinct gene expression profiles and functions. These studies have lead to their identification of a major TFH subset associated with the generation of antibody responses after influenza vaccines in humans.