IL-33 promotes transcriptional and metabolic adaptations of tissue-resident Th2 cells

Authors: KANIA, ANNA - Johns Hopkins University School Of Medicine; SANIN, DAVID - Johns Hopkins University School Of Medicine; GU, XINYUE - Johns Hopkins University School Of Medicine; GIDLEY, MIA - Johns Hopkins University School Of Medicine; KOKOSINSKI, ERYK - Johns Hopkins University School Of Medicine; Smith, Allen; PEARCE, ERIKA - Johns Hopkins University School Of Medicine; PEARCE, EDWARD - Johns Hopkins University School Of Medicine

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/20/2026
Publication Date: 4/16/2026
Citation: Kania, A.K., Sanin, D.E., Gu, X., Gidley, M., Kokosinski, E., Smith, A.D., Pearce, E.L., Pearce, E.J. 2026. IL-33 promotes transcriptional and metabolic adaptations of tissue-resident Th2 cells. Journal of Immunology. 215(4). Article vkag028. https://doi.org/10.1101/2025.07.09.663905.
DOI: https://doi.org/10.1101/2025.07.09.663905

Interpretive Summary: The immune response to parasites and allergens is comprised of two arms, the innate and adaptive components. A key feature of the adaptive response is the change of naïve CD4+ T cells, important to mounting an immune response, into T helper type 2 (Th2) cells, a process that occurs in a special tissue called a lymph node and is completed when the cells invade the infected tissue. It is well-established that naïve CD4+ T cell activation requires changes to how they produce energy to meet the energy demands of cellular growth and differentiation. However, the energy requirements associated with the transition to moving into the tissue remain poorly understood. To address this, we compared the response of pre-Th2 cells (recovered from parasite infected mice) to stimulation with a two types of proteins that stimulate immune cells called IL-33 and anti-CD3/anti-CD28. We found that IL-33, but not anti-CD3/CD28, increased populations of Th2 cells exhibiting characteristics of mature tissue-resident Th2 cells, such as expression of IL-33 receptor (ST2), TSLP receptor, and Amphiregulin. We found that IL-33 induced changes in the metabolism of the amino acid arginine which is linked to mTORC1 activation and polyamine synthesis (important metabolic pathways) that were required for the development tissue-resident like cells. Furthermore, we found that IL-33 induced changes in genes involved in cell movement and cell adhesion that may be critical for tissue residency. Collectively, our findings provide insights into the transcriptional and metabolic adaptations of Th2 cells responding to tissue-integration cues.

Technical Abstract: The polarization of naïve CD4+ T cells into Th2 cells is initiated in lymphoid organs and completed as the cells become tissue resident, where they express ST2, the receptor for the alarmin IL-33, which may be a key signal for tissue integration. Cellular metabolic requirements associated with this transition remain poorly understood. To address this, we compared the response of lymphoid tissue (LT) Th2 cells from helminth parasite-infected mice to stimulation by IL-33 versus through the T cell receptor via anti-CD3/CD28. We found that IL-33, but not anti-CD3/CD28, induced the development of tissue-resident like Th2 cells expressing ST2. This was associated with IL-33 induced changes in arginine metabolism linked to mTORC1 activation and polyamine synthesis, which were required for the development of tissue-resident like Th2 cells. Futhermore, IL-33 induced transcriptional changes in genes involved in chemotaxis and cell adhesion that may be critical for tissue integration. Our findings provide insights into adaptations of Th2 cells responding to tissue-integration cues.