Anatomical features of anti-viral immunity in the respiratory tract

Abstract

The mucosal surfaces of the lungs are a major portal of entry for virus infections and there are urgent needs for new vaccines that promote effective pulmonary immunity. However, we have only a rudimentary understanding of the requirements for effective cellular immunity in the respiratory tract. Recent studies have revealed that specialized cellular immune responses and lymphoid tissues are involved in the protection of distinct anatomical microenvironments of the respiratory tract, such as the large airways of the nose and the alveolar airspaces. This review discusses some of the anatomical features of anti-viral immunity in the respiratory tract including the role of local lymphoid tissues and the relationship between effector and memory T cells in the airways, the lung parenchyma, and lymphoid organs.

Fig. 1

Structure of NALT. Serial frozen sections of NALT from the decalcified heads of C57BL/6 mice were probed with anti-B220 to identify B cell follicles and the lectin, Ulex europaeus agglutinin (UEA), to identify M cells in the dome epithelium (top panel), anti-CD11c to identify DCs and anti-CD21 to identify follicular DCs (middle panel), anti-PNAd to identify high endothelial venules expressing the peripheral LN addressin and DAPI to counterstain the NALT. The yellow line delineates the nasal epithelium and the black space in the upper right corner of each panel is the lumen of the nasal passage.

Fig. 2

Structure of BALT. Mice were infected with influenza 14 days previously were pulsed with Bromo-deoxy-Uridine (BrdU) for 1 h prior to sacrifice. Serial frozen sections of lungs from influenza-infected mice were probed with anti-B220 to identify B cell follicles and anti-CD21 to identify follicular DCs (upper left panel), anti-B220 to identify B cell follicles and anti-CD11c to identify DCs in the interfollicular regions (lower left panel). Anti-BrdU antibodies were used to identify proliferating B220+ B cells and proliferating CD4+ T cells (upper right panel) as well as B220+ B cells and CD8+ T cells (lower right panel). Note that the two B cell follicles in these sections are separated by an interfollicular region that contains CD11c+ DCs and T cells. These lymphoid structures surround a major airway.

Fig. 3

Recall responses to secondary virus infections occur in phases. The memory CD8+ T-cell response to secondary virus infections is comprised of three distinct phases (upper panel). The first phase of comprised of memory cells already resident in the lung airways (bronchoalveolar lavage cells, BAL) that respond immediately to infection. These cells do not proliferate and are largely eliminated by day 4 of the infection through inflammatory mechanisms. The second phase is the antigen non-specific recruitment of non-proliferating memory cells from the circulation. The numbers of cells peak around day 4 and then decline since this is a non-replicating population. Finally, proliferating effector cells generated by antigen-driven stimulation in the LN are recruited after day 4. The combined response is illustrated in the lower panel, which also indicates the fraction of the response that involves proliferating T cells. Note that the late phase of the combined response indicates that new memory cells persist in the lung airways following resolution of the infection.