Biology subjects

Warren, R. T.

Publications and source records attributed to Warren, R. T..

3 recordsLinked to original sources

bioRxiv2025

Aiolos restricts the generation of antigen-inexperienced, virtual memory CD8+ T cells

CD8+ virtual memory T (TVM) cells are memory-like cells that rapidly respond to infection via antigen-independent bystander effector functions. While it is recognized that TVM cells arise independently of foreign antigen encounter, the mechanisms governing their development are not fully understood. Here, we identify the transcription factor Aiolos as a negative regulator of TVM cells. We observed higher quantities of TVM cells in the spleens of uninfected Aiolos-deficient (Ikzf3-/-) mice relative to wild-type (WT). Furthermore, Ikzf3-/- TVM cells produced higher levels of IFN-{gamma} and granzyme B. In addition, we found that Ikzf3-/- TVM cells accumulated to higher quantities in the lungs within 24 hours of influenza virus infection. In line with enhanced TVM functional capacity and lung trafficking, Aiolos-deficient mice cleared virus more rapidly and exhibited reduced morbidity relative to WT animals. Mechanistically, we observed that Aiolos represses the TVM transcriptional regulator Eomes and the IL-15R subunit CD122 (IL-15R{beta}/IL-2R{beta}), known contributors of TVM cell generation. Collectively, these findings establish Aiolos as a novel molecular repressor of TVM generation and function.

immunology↗

bioRxiv2022

Eos promotes TH2 differentiation by propagating the IL-2/STAT5 signaling pathway.

The Ikaros zinc finger transcription factor Eos has been commonly implicated in regulatory T cells to promote their immunosuppressive functions. Paradoxically, a new role is emerging for Eos in promoting pro-inflammatory responses of conventional CD4+ T cells in the dysregulated setting of autoimmunity. Even so, the precise role of Eos in regulating the differentiation and function of healthy effector CD4+ T cell subsets remains unclear. Here, we find that Eos is a positive regulator of CD4+ T helper 2 (TH2) cells--effector T cells implicated in the induction of allergic asthma. Using murine in vitro TH2 cells and an in vivo house dust mite asthma model, we found that Eos-deficient T cells had reduced expression of key TH2 transcription factors, effector cytokines, and differentiation receptors. Mechanistically, among various TH2-polarizing pathways, the IL-2/STAT5 axis and its downstream TH2 gene targets emerged as one of the most significantly downregulated networks in Eos deficiency. Using in vitro TH2 cells and overexpression of Eos zinc-finger-domain mutants, we discovered that Eos forms a novel complex with and supports the tyrosine-phosphorylated signaling activity of STAT5. Overall, these data define a novel regulatory mechanism whereby Eos promotes IL-2/STAT5 activity to facilitate TH2 differentiation.

immunology↗

bioRxiv2022

Aiolos modulates the TFH and CD4-CTL differentiation programs via reciprocal regulation of the Zfp831/TCF-1/Bcl-6 axis and CD25

Effective immunity to influenza virus and other respiratory viruses requires the generation of CD4+ T cell subsets that coordinate multiple aspects of the immune response. These subsets include T follicular helper (TFH) and T helper 1 (TH1) cells, which promote humoral and cell-mediated responses, respectively. A third population, CD4+ cytotoxic T lymphocytes (CD4-CTLs) facilitates clearance of infection via mechanisms normally associated with CD8+ T cells. Here, we identify the transcription factor Aiolos as a regulator of TFH and CD4-CTL responses. We demonstrate that Aiolos deficiency compromises TFH differentiation and antibody production during influenza virus infection. Conversely, we find that CD4+ T cells acquire a cytotoxic-like program in the absence of Aiolos, including increased expression of the CTL-associated transcription factors Eomes and Blimp-1. We further show that while Aiolos positively regulates the TFH transcriptional regulators Zfp831, TCF-1 and Bcl-6, it also directly represses expression of IL-2R and IL-2/STAT5-driven expression of the cytotoxic gene program. Thus, our findings identify Aiolos as a pivotal regulator of TFH and CD4-CTL differentiation and highlight its potential as a target for manipulating CD4+ T cell humoral and cytotoxic responses.

immunology↗