Multiple studies have identified Interleukin-6 (IL-6) and Transforming Growth Factor-beta;1 (TGF-β1) as sufficient to induce T helper type-17 (TH17) differentiation in vitro, but it is unclear whether these factors are necessary, and if so, what the cellular source of these factors is in the context of a TH17 inducing infection in vivo. Moreover, studies of the TH17 response have focused mainly on the effector phase and it is currently unclear whether these cells persist into the memory phase. To address these questions, we used mouse models of immunity to the extracellular bacterium Group A Streptococcus pyogenes (GAS) and the intracellular bacterium Listeria monocytogenes (LM), along with a sensitive peptide:Major Histocompatibility Complex II (pMHCII) tetramer and magnetic bead-based enrichment method to study the differentiation of naïve, polyclonal, GAS or LM pMHCII-specific CD4+ cells into TH17 cells. We found that an intranasal route of infection resulted in TH17 differentiation, while an intravenous route of infection resulted in T helper-type 1 (TH1) differentiation after either GAS or LM infection. We also found that IL-6 and TGF-beta;1 were necessary for TH17 differentiation in response to intranasal GAS infection in vivo. We identified a hematopoietic source of IL-6 and a dendritic cell source of TGF-beta;1 necessary for this differentiation. Lastly, we found that intravenous LM infection induced a long-lived TH1 memory population, while intranasal LM infection induced a short-lived TH17 population. Combined, this work supports a model whereby dendritic cells residing in upper respiratory tissues induce TH17 cell differentiation through the production of IL-6 and TGF-beta;1, resulting in a short-lived population of TH17 cells.
University of Minnesota Ph.D. dissertation. September 2012. Major: Microbiology, Immunology and Cancer Biology. Advisor:Marc K. Jenkins, Ph.D. 1 computer file (PDF); viii, 112 pages.
Linehan, Jonathan L..
The generation and maintenance of T Helper 17 cells in response to bacterial infection.
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