SFB 1054 Seminar - Shaun McColl

Title: CCR2 and T lymphocyte biology

Appropriate execution of T lymphocyte effector and memory function requires their precise and coordinated migration to specific lymphoid niches and peripheral effector sites. This migration is largely controlled by expression of chemokine receptors. Our research shows important and diverse roles for CCR2, a receptor previously associated almost exclusively with mononuclear phagocyte function, in T lymphocyte biology.

IL-17-producing CD4⁺ T (Th17) and γδ (γδT17) cells are critical for host defence against extracellular pathogens but also contribute to numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFNγ-producing Th17 cells. We show that migration of these subsets is controlled by a unique temporally-regulated IL-23-dependent switch from CCR6 to CCR2 that is critical for pathogenic Th17 cell-driven inflammation in EAE. This switch defines a unique in vivo cell surface signature (CCR6^-ve CCR2^+ve) of GM-CSF/IFNγ-producing Th17 cells in EAE, persistent extracellular bacterial infection, and in multiple sclerosis in humans.

CCR6 and CCR2 are also both critical for the function of γδT17 cells although the regulation of expression and function of these receptors differs to that of Th17 cells. While CCR6 recruits resting γδT17 cells to the dermis, CCR2 drives rapid recruitment of γδT17 cells to inflamed tissues in models of autoimmunity, cancer and infection. Activation-induced downregulation of CCR6 is required for optimal recruitment of γδT17 cells to inflamed tissue by preventing sequestration into uninflamed dermis.

Memory CD8⁺ T cells are important for controlling reinfection against intracellular pathogens, yet the migratory signals required for CD8⁺T cell memory formation are poorly understood. In this study, we show that the chemokine receptor CCR2 is expressed on CD8⁺ T cells following influenza A infection. CCR2-deficient antigen-specific CD8⁺ T cells displayed normal effector cell differentiation and cytokine production but impaired development of memory precursor cells. Furthermore, CCR2^-/- CD8⁺ T cells had reduced proliferation only in the late stages of infection. This led to enhanced CD8⁺ T cell contraction alongside a cell intrinsic defect in the formation of central and tissue-resident memory CD8⁺ T cells. Consistent with these observations, CCR2^-/- memory CD8⁺ T cells failed to efficiently control secondary infection against intracellular pathogens.

Together, these observations provide new insights into effector T cell trafficking and T cell memory that depend on dynamic regulation of chemokine receptor expression.

 Shaun McColl - Website

Venue: 

TranslTUM, Center for Translational Cancer Research,

Johannes B. Ortner Forum, Room 22.0.1, EG
Ismaninger Str. 22, 81675 München

Host: Thomas Korn (B06)