Regulation of human T helper cell differentiation [electronic resource]

Naïve CD4+ T cells are precursor cells that differentiate into distinct lineages of T helper (TH) cells upon cellular activation. The work presented here describe how we identified the soluble factors required for the differentiation of human TH17 and TH9 cells, which are two novel TH subsets implicated in the pathogenesis of various autoimmune and allergic disorders, respectively. We also performed functional analysis with human TH1, TH2 and TH17 cells, demonstrating that different TH cells drive monocytes to differentiate into specialized DC subsets. Collectively, we believe that these data have significant implications for the treatment of inflammatory disorders. In order to determine the factors that drive human TH17 differentiation, we hypothesized that a subset of TLR ligands could induce PBMCs to secrete TH17-polarizing factors. We identified that conditioned media from TLR4- and TLR8/7-stimulated cultures could promote IL-17 production. Using a proteomics screening approach, we demonstrated that a combination of pro-inflammatory cytokines synergistically promote human TH17 differentiation. TH17-polarizing cytokines upregulated the expression of the transcription factor ROR[Gamma]t and drove the expansion of memory TH17 and TH1/17 cells. The data presented in Chapter 2 indicate that the pathways driving murine and human TH17 responses are quite different, which may diminish the value of various mouse studies in the treatment of TH17-driven diseases. In collaboration with the laboratory of Edgar Engleman, we demonstrate that TH cells mediate the differentiation of monocytes into distinct DCs. Importantly, TH17 cells drive the formation of TH17-promoting DCs (DCTh17), whereas TH1 and TH2 cells drive the formation of TH1- and TH2-promoting DCs (DCTh1 and DCTh2), respectively. Blocking the TH1 cytokine IFN-[Gamma] inhibited DCTh1 formation, whereas neutralizing the TH2 cytokines IL-4 and IL-13 inhibited DCTh2 formation. Studies of psoriasis and atopic dermatitis skin lesions indicate that TH cells are closely associated with monocytes and DCs in situ, suggesting that this pathway contributes to disease pathogenesis. These data illustrate a positive feedback loop between TH cells, monocytes and DCs that may contribute to the ongoing inflammation observed in various autoimmune and allergic disorders. In Chapter 4, the factors that promote human TH9 differentiation are characterized, and we provide evidence that IL-21 is a potent enhancer of IL-9 secretion. TH9 cells generated in vitro exhibit a heterogeneous phenotype based on the expression of the transcription factors GATA-3 and Foxp3. Finally, a small population of memory CD4+ T cells cultured under TH17-polarizing conditions secreted IL-9, IL-17 and IFN-[Gamma], suggesting considerable lineage plasticity among human TH cells. Taken together, these data indicate a complex cytokine network in the regulation of human TH17 and TH9 cells.

Advisor: Utz Paul primary advisor. Thesis advisor
Engleman Edgar G. advisor. Thesis advisor
Robinson William (William Hewitt) advisor. Thesis advisor
Steinman Lawrence advisor. Thesis advisor