Members of the interferon-induced transmembrane protein (IFITM) family are expressed at a basal level on many types of tissues but are strongly induced by type I interferons. There are four functional IFITM genes in humans and in mice, and these encode proteins that have two transmembrane domains and are localized to various vesicular compartments of the cell. IFITM proteins act to inhibit, or restrict, viruses at early steps of infection. Although the molecular details are unclear, IFITM1 appears to interfere with the fusion of viral membranes with the membrane of the lysosome, which is required for introducing some viral genomes into the cytoplasm. Viruses that must undergo this fusion event in lysosomes, such as the Ebola virus, are restricted by IFITM1. Similarly, IFITM3 interferes with membrane fusion in late endosomes, and so restricts the influenza A virus, which undergoes fusion there. The importance of this mechanism is demonstrated by the increased viral load and higher mortality in mice lacking IFITM3 that are infected with the influenza A virus.
Interferons also stimulate production of the chemokines CXCL9, CXCL10, and CXCL11, which recruit lymphocytes to sites of infection. They also increase the expression of MHC class I molecules on all types of cells, which facilitates recognition of virally infected cells by cytotoxic T lymphocytes via the display of viral peptides complexed to MHC class I molecules on the infected cell surface (see Fig. 1.30). Through these effects, interferons indirectly help promote the killing of virus-infected cells by CD8 cytotoxic T cells. Another way in which interferons act is to activate populations of innate immune cells, such as NK cells, that can kill virus-infected cells, as described below.
3-23 Several types of innate lymphoid cells provide protection in early infection.
A defining feature of adaptive immunity is the clonal expression of antigen receptors, produced by somatic gene rearrangements, that provide the extraordinarily diverse specificities of T and B lymphocytes (see Section 1-11). However, for several decades, immunologists have recognized cells that have lymphoid characteristics but which lack specific antigen receptors. Natural killer (NK) cells have been known the longest, but in the past several years other distinct groups of such cells have been identified. Collectively, these are now called innate lymphoid cells (ILCs) and include NK cells (Fig. 3.37). ILCs develop in the bone marrow from the same common lymphocyte progenitor (CLP) that gives rise to B and T cells. Expression of the transcription factor Id2 (inhibitor of DNA binding 2) in the CLP represses Band T-cell fates, and is required for the development of all ILCs. ILCs are identified by the absence of Tand B-cell antigen receptor and co-receptor complexes, but they express the receptor for IL-7. They migrate from the bone marrow and populate lymphoid tissues and peripheral organs, notably the dermis, liver, small intestine, and lung.