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

Abstract

Naïve 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-focussed modular cytokine responses. Interleukin (IL)-4-induced Gata3 upregulation is important for the T helper 2 (T H 2) cell polarisation 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 naïve CD4 + T cells contributed to pan-T cell activation by promoting T-T cell clustering and IL-2/CD25/STAT5-signalling. Subsequently, IL-4/Gata3-induced selective upregulation of αvβ3 licenced intercellular αvβ3-Thy1 interactions among T H 2 cells, enhanced mTOR signalling, 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 responses.

Fine-Tuning Levels of Filamins A and B as a Specific Mechanism Sustaining Th2 Lymphocyte Functions

“…Furthermore, high expression of ITGAV and ITGB3 transcripts in Th2 lymphocytes correlated with high levels of the α V  3 integrin protein (data herein and 7 ). Taken together, these reinforce the view that the αV3 integrin is critical to Th2 specific functions and antigen-specific lung Th2 cell responses 7,41 .…”

T cells Use Focal Adhesions to Pull Themselves Through Confined Environments

“…More specifically, CD4+ T cell interstitial migration is highly dependent on α v integrin adhesion with ECM [37, 38]. Furthermore, α v β 3 integrins were very recently shown to be essential for efficient adaptative helper T cell immune response, as the inhibition of α v β 3 completely impaired adaptative immune response [39]. The contrast in these findings highlights the need to understand the molecular mechanisms that underlie immune cell migration.…”

CD90 is not constitutively expressed in functional innate lymphoid cells

“…Moreover, in addition to CD90 high CD8 + T cells, splenic CD90 - and CD90 low CD8 + T cells are also a relevant source of IFNγ in a mouse model of LCMV infection ( 73 ). The CD90 extracellular domain has binding sites for αvβ3 and syndecan-4, which may be the basis of a reported in trans interaction of CD90 with αvβ3 and syndecan-4 expressed on other cells ( 4 , 74 ). Indeed, the interaction between CD90 and αvβ3 was functional in CD4 T cells in terms of promoting the differentiation of Th2 cells ( 74 ).…”

“…The CD90 extracellular domain has binding sites for αvβ3 and syndecan-4, which may be the basis of a reported in trans interaction of CD90 with αvβ3 and syndecan-4 expressed on other cells ( 4 , 74 ). Indeed, the interaction between CD90 and αvβ3 was functional in CD4 T cells in terms of promoting the differentiation of Th2 cells ( 74 ). Binding sites for the in trans interaction with other integrins or CD97 are yet to be characterized.…”