The role of the inflammatory chemokine receptor CCR2 in immune responses to respiratory viral infection
Effector and memory CD8⁺ T cells are critical for the elimination of primary intracellular infections, and for providing rapid immunity upon re-infection. The T cells responding to an infection can take on disparate fates. Although many factors have been described that influence the generation of effector and memory cells, how T cells are polarised to a particular fate is poorly understood. One factor that is important for T cell fate decisions in the microanatomical localisation of activated T cells in specific niches that promote T cell differentiation, and this activity is regulated through the specific action of chemokines and chemokine receptors. However, the molecular mechanisms underlying these processes are unclear. Understanding the regulation of CD8⁺ T cell traffcking should reveal key mechanisms in T cell differentiation and protective immunity, and this knowledge would have wide-ranging impacts on the development of vaccines against intracellular pathogens like influenza, where antibody responses provide only short-term protection, and against emerging intracellular pathogens. Thus, the regulation of CD8⁺ T cell traffcking during infection was investigated by focusing on chemokine receptors, which orchestrate lymphocyte migration. The expression of chemokine receptors was investigated in CD8⁺ T cells responding to influenza infection. This revealed that the chemokine receptor CCR2 was highly expressed in CD8⁺ T cells in the mLN, spleen, peripheral blood, and lung parenchyma. Further investigation revealed that CCR2 was expressed within the first T cell division in the mLN, and maintained broad and high expression across all effector and memory T cell subsets. Despite the high expression of CCR2 across CD8⁺ T cell effector and memory subsets, the receptor was dispensable for CD8⁺ T cell differentiation, acquisition of effector potential, and expansion and traffking during viral challenge. Further investigation into the role of CCR2 on circulating memory T cells however, did uncover a potential role for CCR2 in the optimal immunosurveillance of damaged or stressed peripheral tissue during sterile inflammation. Further investigation into the requirement for host CCR2 in protection from influenza infection revealed a cell-extrinsic requirement for CCR2 in optimal memory T cell function during influenza challenge. Although host deficiency of Ccr2 had no impact on the development of memory T cell populations after primary A/HK-x31 infection, these mice displayed increased morbidity during a lethal A/PR8-challenge and increased viral titres in the lungs relative to their WT counterparts. This was associated with a reduction in the re-expansion of influenza-specific memory CD8⁺ T cells in the lungs. Concomitant with this reduction in T cell proliferation was a reduction in the number of monocytes and monocyte-derived cells, and an inflammatory cDC subset in the lungs. This project demonstrates that the chemokine receptor CCR2 is dispensable for any cell-intrinsic role in CD8+ T cell effector or memory cell differentiation and traffcking during viral infection. However, evidence for a cell-intrinsic role for CCR2 in the optimal immunosurveillance of peripheral tissue in certain contexts of sterile inflammation is provided. Additionally, this project demonstrates a cellextrinsic role for CCR2 in shaping optimal re-call responses to a heterosubtypic influenza challenge. These findings provide a framework for the better understanding of memory T cell re-activation and immune protection at the site of infection and inflammation.
Infection, inflammation, monocyte, chemokine, chemokine receptor, CCR2, CCL2
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