Immunity to Influenza is dependent on MHC II polymorphism: study with 2 HLA transgenic strains

David Luckey,Daniel D Billadeau,Douglas G Osborne,Eric A Weaver,Veena Taneja

doi:10.1038/s41598-019-55503-1

Abstract

Major histocompatibility complex II (MHC II) molecules are involved in antigen presentation and the development of a functional adaptive immune response. Evolutionary selection for MHC molecules that effectively clear infectious agents provides an advantage to humans. However, certain class II molecules are associated with autoimmune diseases. In this study we infected autoimmune-susceptible DRB1*0401.AEo and non-susceptible *0402.AEo mice with H1N1 influenza and determined clearance and protective immunity to H3N2 virus. *0401 mice generated a robust TLR-triggered immune response and cleared H1N1 influenza virus infection. After vaccination and challenge with H1N1, *0401 mice, when challenged with H3N2, generated cross-protective immunity to heterosubtypic H3N2 influenza strain whereas *0402 mice cleared the H1N1 infection but did not generate cross-protective immunity against the H3N2 influenza strain. The intracellular trafficking route of MHCII revealed that *0401 molecules traffic through the late endosome/lysosomes while *0402 molecules traffic into early endosomes. This suggested that trafficking of MHCII could affect the functional output of the innate immune response and clearance of viral infections. Also, DRB1*0401 mice live longer than HLA-DRB1*0402 mice. The study provides a potential hypothesis for evolutionary selection of *0401 molecule, even though it is associated with autoreactivity, which may be dependent on the availability of peptide repertoire of self-antigens.

Highlights

Major histocompatibility complex II (MHC II) molecules are involved in antigen presentation and the development of a functional adaptive immune response
This is supported by the observations showing that HLA-DR4 was significantly associated with the clearance of hepatitis B virus infection[5], even though DR4 is associated with susceptibility to rheumatoid arthritis (RA)
This is supported by our previous work with transgenic mice expressing HLA-DRB1*0401 genes, which develop inflammatory arthritis that mimics human RA in disease histopathology, autoantibodies and sex-bias[8] while DRB1*0402 expressing mice are protected from arthritis[9]

Summary

Introduction

Major histocompatibility complex II (MHC II) molecules are involved in antigen presentation and the development of a functional adaptive immune response. Major histocompatibility complex (MHC) class II molecules present peptides to T cells leading to generation of immune responses to pathogens. To define the role of MHC II genes, we have generated transgenic mice expressing human HLA class II genes associated with autoimmune diseases but lacking endogenous class II molecules. The data presented here describes the advantage RA-associated *0401 molecules provide over *0402 in clearing infection even though a difference in trafficking leads to binding self-antigens which may cause autoimmunity. We show that *0401 molecules traffic through the late endosome/lysosome while *0402 predominantly enters the early endosome This difference in intracellular trafficking routes could result in differential antigen presentation and an increase in association with autoimmunity

Methods

Findings

Conclusion