Negative Selection by an Endogenous Retrovirus Promotes a Higher-Avidity CD4+ T Cell Response to Retroviral Infection

Abstract

Effective T cell responses can decisively influence the outcome of retroviral infection. However, what constitutes protective T cell responses or determines the ability of the host to mount such responses is incompletely understood. Here we studied the requirements for development and induction of CD4+ T cells that were essential for immunity to Friend virus (FV) infection of mice, according to their TCR avidity for an FV-derived epitope. We showed that a self peptide, encoded by an endogenous retrovirus, negatively selected a significant fraction of polyclonal FV-specific CD4+ T cells and diminished the response to FV infection. Surprisingly, however, CD4+ T cell-mediated antiviral activity was fully preserved. Detailed repertoire analysis revealed that clones with low avidity for FV-derived peptides were more cross-reactive with self peptides and were consequently preferentially deleted. Negative selection of low-avidity FV-reactive CD4+ T cells was responsible for the dominance of high-avidity clones in the response to FV infection, suggesting that protection against the primary infecting virus was mediated exclusively by high-avidity CD4+ T cells. Thus, although negative selection reduced the size and cross-reactivity of the available FV-reactive naïve CD4+ T cell repertoire, it increased the overall avidity of the repertoire that responded to infection. These findings demonstrate that self proteins expressed by replication-defective endogenous retroviruses can heavily influence the formation of the TCR repertoire reactive with exogenous retroviruses and determine the avidity of the response to retroviral infection. Given the overabundance of endogenous retroviruses in the human genome, these findings also suggest that endogenous retroviral proteins, presented by products of highly polymorphic HLA alleles, may shape the human TCR repertoire that reacts with exogenous retroviruses or other infecting pathogens, leading to interindividual heterogeneity.

HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates

“…A recent study has provided evidence that, in mice, an endogenous retroviral antigen with homology to Friend murine leukemia virus (F-MLV) drives negative selection of the naive CD4 + T cell repertoire available to respond to a specific F-MLV-Env determinant (31). The result of this is the deletion of low-avidity cross-reactive T cells and the promotion of a higher avidity to CD4 + T cell responses to retroviral infection.…”

Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus

“…Inbred B6 and CD45.1 + congenic B6 (B6.SJL- Ptprc a Pep3 b /BoyJ) mice, TCRβ-transgenic EF4.1 mice (Antunes et al., 2008), TCRαβ doubly transgenic EVα2 mice (Merkenschlager et al., 2016), Rag1-deficient ( Rag1 −/− ) mice (Mombaerts et al., 1992), B cell-receptor-deficient ( Ighm −/− ) mice (Kitamura et al., 1991), mice with an activatable YFP gene targeted into the Gt(ROSA)26Sor ( R26 ) locus (Srinivas et al., 2001), mice with a targeted insertion of Cre recombinase into the Tnfrsf4 locus (Klinger et al., 2009) ( Tnfrsf4 Cre ), mice with a conditional Bcl6 allele (Kaji et al., 2012) ( Bcl6 fl ), endogenous ecotropic murine-leukemia-virus-deficient ( Emv2 −/− ) mice (Young et al., 2012), mice with a targeted insertion of GFP into the Prdm1 locus (Kallies et al., 2009) (Blimp1-GPF), and mice with a targeted insertion of tdTomato fluorescent protein into the Gzmb locus (Mouchacca et al., 2013) (GzmB-tdTomato) were all on the B6 genetic background and were maintained at the Francis Crick Institute’s animal facilities. All animal experiments were approved by the ethical committee of the Francis Crick Institute and were conducted according to local guidelines and UK Home Office regulations under the Animals (Scientific Procedures Act) 1986 (ASPA).…”

Mammalian Endogenous Retroviruses

“…This strategy has been used on multiple occasions in a number of different species, including mice, chickens, cats, and sheep, with a variety of ERVs (156,157,158). Under certain circumstances, endogenous Env protein expression may also act to modulate immune responses to infection by acting as a selfantigen (159). Interestingly, as well as blocking infection of its exogenous counterpart by receptor interference, at least two loci of endogenous Jaagsiekte sheep retrovirus (enJSRV) encode defective Gag proteins that act in a dominant-negative way to block late stages of virus replication (160).…”