Genome-wide CRISPR screen reveals a key role for integrin avb3 in TH2 cell polarisation [CRISPRscr]

T helper 2 (TH2) cells play critical roles in protective immunity against parasitic helminth infections and in tissue repair. However, misdirected TH2 cell responses promote allergy and asthma. Using whole-genome CRISPR-Cas9 screens in developing TH2 cells we defined a functional TH2ome for TH2 differentiation and validated a diverse array of molecules not previously linked to TH2 cell development and function. Strikingly, we discovered that integrin avb3 plays a key and previously unappreciated role in the differential polarisation of TH2 cells and their type 2 cytokine expression. Conversely, we did not identify the LFA-1 integrin which mediates inside-out signalling following TCR ligation as part of the T cell synapse and preferentially promotes TH1 differentiation. We find that TH2 cell expression of integrin avb3 is required for the formation of TH2 cell clusters that exhibit enhanced T cell activation, promoting proliferation and TH2 cell differentiation, and thereby potentiating antigen-driven TH2 cell responses. Overall design: Transcriptomic analyses of sorted T helper cell populations with CRISPR- or flox mediated knockout.