The IFITM protein family in adaptive immunity

Abstract

Interferon-inducible transmembrane (IFITM) proteins are a family of small homologous proteins, localized in the plasma and endolysosomal membranes, which confer cellular resistance to many viruses. In addition, several distinct functions have been associated with different IFITM family members, including germ cell specification (IFITM1-IFITM3), osteoblast function and bone mineralization (IFITM5) and immune functions (IFITM1-3, IFITM6). IFITM1-3 are expressed by T cells and recent experiments have shown that the IFITM proteins are directly involved in adaptive immunity and that they regulate CD4⁺ T helper cell differentiation in a T-cell-intrinsic manner. Here we review the role of the IFITM proteins in T-cell differentiation and function.

Keywords: T cell; T helper type 1; T helper type 2; differentiation; interferon-inducible transmembrane protein.

Figure 1

Chromosomal position of interferon‐inducible transmembrane (IFITM) genes, IFITM topology and cellular localization. (a) The cartoon illustrates the location and organization of IFITM gene clusters in mouse and human. Introns are represented by a horizontal brown rectangle. Exons are represented by vertical coloured rectangles, arrows below indicate the direction of transcription.4, 18 (b) The cartoon illustrates the proposed models of IFITM protein topology. First model suggests a conserved intracellular loop (CIL) between two transmembrane domains (TM) with extracellular C' and N' terminal domains. Second model shows a CIL between two intramembrane domains (IM) with intracellular C' and N' terminal domains. The third model proposes a CIL between IM and a TM with an intracellular N' and an extracellular C' terminal domain. These three topology models are predominant but alternative models have been proposed for specific IFITM protein topology depending on their function.1 (c) The cartoon illustrates the cellular localization of IFITM1–3 proteins. IFITM proteins have been shown to span several cellular membranes. IFITM1 is found in different intracellular compartments from IFITM2 and IFITM3 with little overlap.47, 59 IFITM1–3 can all be found on the plasma membrane, but IFITM1 has been shown to be the predominant IFITM associated with the plasma membrane and is also found in early endosomes.35, 60 IFITM2 and IFITM3 are predominately located intracellularly in late endosomes and lysosomes and co‐localize with Rab7, CD63 and lysosomal‐associated membrane protein (LAMP1).21 The illustrations in this figure are cartoons that are not drawn to scale.

Figure 2

Interferon‐inducible transmembrane (IFITM) proteins are involved in T helper type 1 (Th1) and Th2 differentiation. Cartoons show a not‐to‐scale graphical representation of the role of IFITM proteins in the regulation of Th1/Th2 differentiation.13 (a) In normal conditions, differential expression of IFITM proteins maintains the normal balance between Th1 and Th2 differentiation on activation of naive CD4⁺ T cells. (b) Upper panel: In the absence of IFITM proteins, the balance of the Th1/Th2 differentiation is altered on activation of naive CD4⁺ T cells. Differentiation of Th1 cells is promoted with higher expression of key Th1 regulators, while Th2 differentiation is suppressed. Lower panel: IFITM deficiency decreases allergic airway inflammation, with lower cellular infiltration, mucous secretion, and Th2 response in a mouse model of allergic airway disease (asthma).