Abstract
MHCII molecules are heterodimeric cell surface proteins composed of an α and β chain. These molecules are almost exclusively expressed on thymic epithelium and antigen presenting cells (APCs) and play a central role in the development and function of CD4 T cells. Various MHC-II knockout mice have been generated including MHC-IIAα-/- (I-Aα-/-), MHC-IIAβ-/- (I-β-/-) and the double knockout (I-Aαxβ-/-). Here we report a very striking observation, namely that alphaviruses including the avirulent strain of Semliki Forest virus (aSFV), which causes asymptomatic infection in wild-type C57BL6/J (B6) mice, causes a very acute and lethal infection in I-Aα-/-, but not in I-β-/- or I-Aαxβ-/-, mice. This susceptibility to aSFV is associated with high virus titres in muscle, spleen, liver, and brain compared to B6 mice. In addition, I-Aα-/- mice show intact IFN-I responses in terms of IFN-I serum levels and IFN-I receptor expression and function. Radiation bone marrow chimeras of B6 mice reconstituted with I-Aα-/- bone marrow expressed B6 phenotype, whereas radiation chimeras of I-Aα-/- mice reconstituted with B6 bone marrow expressed the phenotype of high viral susceptibility. Virus replication experiments both in vivo and in vitro showed enhanced virus growth in tissues and cell cultures derived form I-Aα-/- compared to B6 mice. This enhanced virus replication is evident for other alpha-, flavi- and poxviruses and may be of great benefit to producers of viral vaccines. In conclusion, I-Aα-/- mice exhibit a striking susceptibility to virus infections independent of their defective MHC-II expression. Detailed genetic analysis will be carried out to characterise the underlining genetic defects responsible for the observed phenomenon.
Highlights
The interplay between the innate and the adaptive arms of the immune system is essential for the establishment of protective immunity against harmful microbial infections
Helper and regulatory functions of CD4+ T cells involve antigen recognition through their TCRs, which recognize processed peptide antigens presented by antigen presenting cells (APCs) in the context of major histocompatibility complex class II (MHC-II) molecules
We report that avirulent SFV, which only causes asymptomatic infection in adult wild-type C57BL6/J (B6) mice, caused a very acute and lethal infection in I-Aa-/- mice
Summary
The interplay between the innate and the adaptive arms of the immune system is essential for the establishment of protective immunity against harmful microbial infections. We found this susceptibility to be unrelated to the lack of functional MHC-II expression, but associated with increased virus replications in various tissues. Our data show high expression levels of MHC-II molecules on CD19+ cells from B6 mice compared to that from I-Aa-/- mice (Figure 1a).
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