An αvβ3 integrin checkpoint is critical for efficient TH2 cell cytokine polarization and potentiation of antigen-specific immunity

• Published in: Nature immunology Vol. 24; no. 1; pp. 123 - 135
• Main Authors: Szeto, Aydan C. H., Ferreira, Ana C. F., Mannion, Jonathan, Clark, Paula A., Sivasubramaniam, Meera, Heycock, Morgan W. D., Crisp, Alastair, Jolin, Helen E., Kozik, Patrycja, Knolle, Martin D., McKenzie, Andrew N. J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-01-2023; Nature Publishing Group
• Subjects: 631/250/127/1213; 631/250/1619/554/1898/1274; Allergens; Antigens; Biomedical and Life Sciences; Biomedicine; CD25 antigen; CD4 antigen; Cell activation; Cell differentiation; CRISPR; Cytokines; GATA-3 protein; Genomes; Helper cells; Hypersensitivity; Immunology; Infectious Diseases; Inflammation; Interleukin 13; Interleukin 2; Interleukin 4; Interleukin 5; Lymphocytes; Lymphocytes T; Polarization; Rapamycin; Stat5 protein; TOR protein
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-022-01378-w

Naive CD4
+
T lymphocytes initially undergo antigen-specific activation to promote a broad-spectrum response before adopting bespoke cytokine expression profiles shaped by intercellular microenvironmental cues, resulting in pathogen-focused modular cytokine responses. Interleukin (IL)-4-induced Gata3 upregulation is important for the helper type 2 T cell (T
H
2 cell) polarization associated with anti-helminth immunity and misdirected allergic inflammation. Whether additional microenvironmental factors participate is unclear. Using whole mouse-genome CRISPR–Cas9 screens, we discovered a previously unappreciated role for αvβ3 integrin in T
H
2 cell differentiation. Low-level αvβ3 expression by naive CD4
+
T cells contributed to pan-T cell activation by promoting T–T cell clustering and IL-2/CD25/STAT5 signaling. Subsequently, IL-4/Gata3-induced selective upregulation of αvβ3 licensed intercellular αvβ3–Thy1 interactions among T
H
2 cells, enhanced mammalian target of rapamycin (mTOR) signaling, supported differentiation and promoted IL-5/IL-13 production. In mice, αvβ3 was required for efficient, allergen-driven, antigen-specific lung T
H
2 cell responses. Thus, αvβ3-expressing T
H
2 cells form multicellular factories to propagate and amplify T
H
2 cell responses.
Gata3 upregulation is required for T
H
2 cell polarization. McKenzie and colleagues find that integrin αvβ3 is upregulated by Gata3 and that this is crucial in inducing FAK–mTOR signaling required for T
H
2 cell differentiation.