An alpha v beta 3 integrin checkpoint is critical for efficient T(H)2 cell cytokine polarization and potentiation of antigen-specific immunity

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 alpha v beta 3 integrin in T(H)2 cell differentiation. Low-level alpha v beta 3 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 alpha v beta 3 licensed intercellular alpha v beta 3-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, alpha v beta 3 was required for efficient, allergen-driven, antigen-specific lung T(H)2 cell responses. Thus, alpha v beta 3-expressing T(H)2 cells form multicellular factories to propagate and amplify T(H)2 cell responses.