Antiviral B cell and T cell immunity in the lungs

Abstract

Respiratory viruses are frequent causes of repeated common colds, bronchitis and pneumonia, which often occur unpredictably as epidemics and pandemics. Despite those decimating effects on health and decades of intensive research, treatments remain largely supportive. The only commonly available vaccines are against influenza virus, and even these need improvement. The lung shares some features with other mucosal sites, but preservation of its especially delicate anatomical structures necessitates a fine balance of pro- and anti-inflammatory responses; well-timed, appropriately placed and tightly regulated T cell and B cell responses are essential for protection from infection and limitation of symptoms, whereas poorly regulated inflammation contributes to tissue damage and disease. Recent advances in understanding adaptive immunity should facilitate vaccine development and reduce the global effect of respiratory viruses.

Figure 1. The roles of adaptive T cells and B cells in respiratory viral infection.

During acute respiratory viral infection, humoral and cell-mediated immunity act at different points in time to limit disease. Mucosal IgA generated during previous encounter with virus can prevent or limit infection. IgG in the lungs can limit more severe disease. T cells are beneficial in terms of eliminating virus-infected cells; they coordinate a regulated immune response and, as T_FH cells, promote high-affinity durable antibodies. Failure to control viral dissemination can lead to severe disease. T_reg cells restrain effector responses through various mechanisms, including suppressive cytokines (IL-10, IL-35 and TGF-β) and possibly active killing via perforin and granzyme B (GzmB). An overexuberant or poorly regulated immune response can also lead to damaging immunopathology. Kim Caesar/Nature Publishing Group

Figure 2. B cells and antibody in viral infection.

Following antigen recognition, B cells differentiate with the help of cognate CD4⁺ T_FH cells to form antibody-secreting plasma cells and memory B cells. Class switching to IgG and IgA is followed by the secretion of large amounts of high-affinity antibody that can directly neutralize virus, block entry of the virus into the cell, fix complement, promote phagocytosis and allow antibody-dependent cellular cytotoxicity. Once antigen is cleared, a subset of plasma cells differentiate into a long-lived phenotype and migrate to survival niches in the respiratory tract and bone marrow. LLPC, long-lived plasma cell; MHCII, major histocompatibility complex class II. Kim Caesar/Nature Publishing Group

Figure 3. Maintenance of the tissue localization and function of T_RM cells in the mucosa.

Mucosal lymphocyte clusters (MLCs) are formed by T_RM cells after viral infection and act as sensory cells as well as early effector cells during reencounter with pathogens. They are maintained by upregulation of IFITM3, which allows T_RM cells to resist apoptosis during viral infection. Basal levels of IFN-g production by T_RM cells activates tissue macrophages that release CCL5 and CXCL9, which keep the T_RM cells in situ and prevent the migration of cells from the mucosal lymphocyte clusters into the lumen of the airway. 'Polyfunctional' production of IL-2 by T_RM cells activates granzyme B production in natural killer (NK) cells and lymphocytes, whereas tumor-necrosis factor (TNF) activates DCs that carry antigen to regional nodes, thereby initiating the activation of T cells. T_CM cell, central memory T cell; T_EM cell, effector memory T cell. Kim Caesar/Nature Publishing Group