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INTERLEUKIN 2 INDUCIBLE T CELL KINASE (ITK) FINE TUNES T CELL DIFFERENTIATION

Student Name: Orchi Anannya
Student Concentration: Immunology and Infectious Disease
Principal Investigator: Avery August
Degree Conferral Date: December 2023
Committee Member 1: Carolyn Sevier
Committee Member 2: David Holowka
Committee Member 3: Holger Sondermann
Abstract:

Regulation of T cell signal strength by interleukin 2 inducible T cell kinase (ITK) is a critical
component in naïve CD4+ T helper (Th) and T regulatory (Treg) cell development. We
hypothesized that absence of ITK activity will induce a switch in naïve T cell fate. Using ITK
inhibitor CPI-818 (Corvus), we demonstrate that in the absence of ITK, naïve CD4+ T cells in
Th17 conditions fail to generate pro-inflammatory Th17 cells and switch into generating Foxp3+
Treg-like cells. These switched Foxp3+ Treg-like cells resemble the anti-inflammatory Tregs in
their suppressive function and global transcriptomic profile yet differ from both Th17 and Tregs
in their chromatin landscape. We find that the mechanism involves calcium signaling because
the switch response is prevented when intracellular calcium is enhanced by ionomycin
treatment. This was associated with reduced expression of oxidative phosphorylation and
glycolysis markers, reduced phosphorylation of mTOR-S6 signaling molecules and reduced
expression of Th17 transcription factor BATF. We further investigated the effects of CPI-818
in vivo using the house dust mite induced model of allergic asthma, where CPI-818 treatment
post development of lung inflammation significantly reduced the Th17 immune response. Taken
together, we demonstrate that inhibition of ITK under Th17 differentiation conditions in vitro
can induce the switch from pro-inflammatory Th17 to anti-inflammatory Treg cell fate via
calcium signaling. This switch response is not limited to Th17 conditions, and ITK inhibition
under conditions that promote anti-inflammatory T regulatory type 1 cell generation will also
switch T cell fate to generating pro-inflammatory Th1-like cells. Altogether, this is significant
because this potentially provides novel strategies to manipulate ITK and regulate balance of
pro- and anti-inflammatory responses in health and disease.

Publications:

Anannya O, Huang W, August A. ITK signaling regulates a switch between T helper 17 and T regulatory cell lineages via a calciummediated pathway. Preprint. bioRxiv. 2023;2023.04.01.535229. Published 2023 Apr 3. doi:10.1101/2023.04.01.535229