Pulmonary-Resident Memory Lymphocytes: Pivotal Orchestrators of Local Immunity Against Respiratory Infections

Abstract

There is increasing evidence that lung-resident memory T and B cells play a critical role in protecting against respiratory reinfection. With a unique transcriptional and phenotypic profile, resident memory lymphocytes are maintained in a quiescent state, constantly surveying the lung for microbial intruders. Upon reactivation with cognate antigen, these cells provide rapid effector function to enhance immunity and prevent infection. Immunization strategies designed to induce their formation, alongside novel techniques enabling their detection, have the potential to accelerate and transform vaccine development. Despite most data originating from murine studies, this review will discuss recent insights into the generation, maintenance and characterisation of pulmonary resident memory lymphocytes in the context of respiratory infection and vaccination using recent findings from human and non-human primate studies.

Keywords: EVLP; in situ optical imaging; infection; lung; resident memory B cells; resident memory T cells; vaccination.

Figure 1

Pulmonary resident memory lymphocyte formation. 1) Inhaled respiratory pathogen (viral/bacterial) antigens are processed and presented by dendritic cells (DCs) that migrate to the mediastinal lymph node (MLN). 2) DCs prime naïve CD4⁺ and CD8⁺ T cells in MLN with cognate antigen expressed on MHC II and MHC I, respectively, resulting in T cell proliferation. B cells interact with cognate CD4⁺ T cells at the border between the B and T cell zones within Germinal Centres (GCs), becoming short-lived, antibody-secreting plasma cells or early memory B cells (IgM⁺) or enter the GC and undergo somatic hypermutation and isotype switching, with low affinity B cells differentiating into memory cells to ensure a degree of poly-reactivity. High affinity B cells differentiate into long-lived plasma cells and migrate to the bone marrow where they secrete antibodies for decades (9). 3) Stimulation within the MLN leads to the expression of chemokine receptors CXCR3, CXCR6 and CCR5 that enable T cell trafficking to the lung and airways following CXCL9/CXCL10/CXCL11/CXCL16 chemokine gradients. Pulmonary epithelial cells, DCs and macrophages secrete CCR5 and CXCR3 binding chemokines following respiratory infection (10). The CXCR6 ligand, CXCL16, is also expressed by lung bronchial epithelial cells and may also play a role in T cell homing (11). Memory B cells also migrate to the infected lung, following interferon-inducible chemokines CXCL9, CXCL10 and CXCL11 via CXCR3 (12, 13) where they are strategically located for subsequent reinfection. 4) Once entered the lung, effector T cells and short-lived plasma cells help clear infection and undergo apoptosis. A minority of effector T cells differentiate into pulmonary-resident memory T cells (T_RM). IgM⁺ pulmonary-resident memory B cells (B_RM) seed the lung early after infection, followed by isotype-switched B_RM (7). 5) CD8⁺ T_RM accumulate and self-renew in areas undergoing tissue regeneration following infection known as repair-associated memory depots (RAMD) where they seed airway CD8⁺ T_RM, which are ideally located for pathogen clearance in the case of reinfection. 6) CD4⁺ T_RM and B_RM reside within GCs of inducible bronchus-associated lymphoid tissue (iBALT). Associated with prolonged persistence of antigens, iBALT GCs in infected lungs serve as sites for exaggerated B cell proliferation and cross-reactive clonal selection of plasma cells/memory progenitors following B cell/CD4⁺ T_RM interactions (14).

Figure 2

Compartmentalisation of Pulmonary T_RM and B_RM. 1) CD8⁺ T_RM are maintained in repair-associated memory depots (RAMDs) located in peribronchiolar foci in areas previously damaged from primary infection. RAMDs can be identified via the presence of cytokeratin-expressing cell aggregates which contain distal airway stem cells that help reconstruct damaged lung tissue (10). Murine evidence suggests interstitial CD8⁺ T_RM are primarily maintained by a process of homeostatic proliferation and seed airway T_RM, driven by CXCR6 in response to airway CXCL16 (38). 2) CD4⁺ T_RM surround B_RM cell follicles in iBALT located within the pulmonary parenchyma, where prolonged antigen persistence enhances CD4⁺ T_RM/B_RM formation. Just like RAMDs, iBALT requires tissue damage/inflammation for their establishment. CD4⁺ T_RM are then recruited to the alveolar space via CXCL10/CXCR3.

Figure 3

In Situ Optical Imaging of Resident Memory Lymphocytes. Optical endomicroscopy imaging within the lungs may allow for the in situ detection and quantification of resident memory lymphocyte populations. Monitoring numbers following immunization may help reflect vaccine efficacy and immunological memory. Fluorescently tagged ligands or antibodies, capable of binding to specific T_RM/B_RM surface markers, can be delivered to the airways via a bronchoscope to enable visualisation. Using a combination of fluorescent ligands/antibodies could help differentiate resident memory lymphocyte populations.