J Virol . CCR2 Regulates Vaccine-Induced Mucosal T-Cell Memory to Influenza A Virus

[tetano]

J Virol


. 2021 May 5;JVI.00530-21.
doi: 10.1128/JVI.00530-21. Online ahead of print.
CCR2 Regulates Vaccine-Induced Mucosal T-Cell Memory to Influenza A Virus


Woojong Lee ¹ , Brock Kingstad-Bakke ¹ , Ross M Kedl ² , Yoshihiro Kawaoka ¹ , M Suresh ³



Affiliations

• PMID: 33952647
• DOI: 10.1128/JVI.00530-21

Abstract

Elicitation of lung tissue-resident memory CD8 T cells (T_RMs) is a goal of T-cell based vaccines against respiratory viral pathogens, such as influenza A virus (IAV). Chemokine receptor 2 (CCR2)-dependent monocyte trafficking plays an essential role in the establishment of CD8 T_RMs in lungs of IAV-infected mice. Here, we used a combination adjuvant-based subunit vaccine strategy that evokes multifaceted (T_C1/T_C17/T_H1/T_H17) IAV nucleoprotein-specific lung T_RMs, to determine whether CCR2 and monocyte infiltration are essential for vaccine-induced T_RM development and protective immunity to IAV in lungs. Following intranasal vaccination, neutrophils, monocytes, conventional DCs and monocyte-derived dendritic cells internalized and processed vaccine antigen in lungs. We found that Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF-3)-dependent DCs were essential for eliciting T cell responses, but CCR2 deficiency enhanced the differentiation of CD127^HI/KLRG-1^LO, OX40^+veCD62L^+ve and mucosally imprinted CD69^+veCD103^+ve effector and memory CD8 T cells in lungs and airways of vaccinated mice. Mechanistically, increased development of lung T_RMs, induced by CCR2 deficiency was linked to dampened expression of T-bet, but not altered TCF-1 levels or T cell receptor signaling in CD8 T cells. T1/T17 functional programming, parenchymal localization of CD8/CD4 effector and memory T cells, recall T cell responses and protective immunity to a lethal IAV infection were unaffected in CCR2-deficient mice. Taken together, we identified a negative regulatory role for CCR2 and monocyte trafficking in mucosal imprinting and differentiation of vaccine-induced T_RMs. Mechanistic insights from this study may aid the development of T-cell-based vaccines against respiratory viral pathogens including IAV and SARS-CoV-2.ImportanceWhile antibody-based immunity to influenza A virus (IAV) is type and sub-type specific, lung and airway-resident memory T cells that recognize conserved epitopes in the internal viral proteins are known to provide heterosubtypic immunity. Hence, broadly protective IAV vaccines need to elicit robust T-cell memory in the respiratory tract. We have developed a combination adjuvant-based IAV nucleoprotein vaccine that elicits strong CD4 and CD8 T cell memory in lungs and protects against H1N1 and H5N1 strains of IAV. In this study, we examined the mechanisms that control vaccine-induced protective memory T cells in the respiratory tract. We found that trafficking of monocytes into lungs might limit the development of anti-viral lung-resident memory T cells, following intranasal vaccination. These findings suggested that strategies that limit monocyte infiltration can potentiate vaccine-induced frontline T-cell immunity to respiratory viruses, such as IAV and SARS-CoV-2.