Salmonella polarises peptide‐MHC‐II presentation towards an unconventional Type B CD4⁺T‐cell response

Abstract

Distinct peptide-MHC-II complexes, recognised by Type A and B CD4+ T-cell subsets, are generated when antigen is loaded in different intracellular compartments. Conventional Type A T cells recognize their peptide epitope regardless of the route of processing, whereas unconventional Type B T cells only recognise exogenously supplied peptide. Type B T cells are implicated in autoimmune conditions and may break tolerance by escaping negative selection. Here we show that Salmonella differentially influences presentation of antigen to Type A and B T cells. Infection of bone marrow-derived dendritic cells (BMDCs) with Salmonella enterica serovar Typhimurium (S. Typhimurium) reduced presentation of antigen to Type A T cells but enhanced presentation of exogenous peptide to Type B T cells. Exposure to S. Typhimurium was sufficient to enhance Type B T-cell activation. Salmonella Typhimurium infection reduced surface expression of MHC-II, by an invariant chain-independent trafficking mechanism, resulting in accumulation of MHC-II in multi-vesicular bodies. Reduced MHC-II surface expression in S. Typhimurium-infected BMDCs correlated with reduced antigen presentation to Type A T cells. Salmonella infection is implicated in reactive arthritis. Therefore, polarisation of antigen presentation towards a Type B response by Salmonella may be a predisposing factor in autoimmune conditions such as reactive arthritis.

Unconventional T‐cell recognition of an arthritogenic epitope of proteoglycan aggrecan released from degrading cartilage

“…Alternatively, exogenous peptides were shown to bind to mature MHC II molecules in early endosomes or at the APC surface in the absence of functional H2‐DM, resulting in formation of a mixture of type A and type B T‐cell conformers . Infection of mice with Salmonella typhimurium has also been shown to bias HEL presentation by dendritic cells (DC) towards a type B T‐cell response by a Dectin‐1‐dependent mechanism . Furthermore, mice expressing endogenous HEL were used to show that type B T cells escape negative selection during thymic development in vivo , whereas the majority of type A T cells are deleted, creating a scenario in which self‐reactive type B T cells could persist in peripheral lymphoid organs.…”

The Salmonella Effector SteD Mediates MARCH8-Dependent Ubiquitination of MHC II Molecules and Inhibits T Cell Activation

“…Several groups have shown that Salmonella inhibits surface presentation of MHCII (Cheminay et al., 2005, Halici et al., 2008, Jackson et al., 2013, Lapaque et al., 2009a, Mitchell et al., 2004). This was attributed to the SPI-2 T3SS (Cheminay et al., 2005, Mitchell et al., 2004) and the actions of several effectors that interfere with vesicular trafficking (Cheminay et al., 2005, Halici et al., 2008).…”

“…Mutant strain analysis showed that several effectors affecting vesicular trafficking disrupt T cell proliferation (Cheminay et al., 2005, Halici et al., 2008). Another study revealed that in Salmonella- infected cells, surface levels of mMHCII are reduced through its ubiquitination (Jackson et al., 2013, Lapaque et al., 2009a). However, the effector(s) and mechanisms involved in the regulation of mMHCII ubiquitination are unknown.…”

Recognition of Salmonella by Dectin‐1 induces presentation of peptide antigen to type B T cells

“…Typhimurium results in an increase in presentation of exogenous peptide to type B T cells . The effect required direct contact between the bacteria and APC . To determine if the phenomenon was induced through recognition by PRRs, we exposed murine BMDCs to a panel of PAMPs and examined presentation to the type B T‐cell hybridoma, 11A10.…”

“…Typhimurium (HKST) led to reduced presentation of peptide and native Ag to type A T cells. Presentation of peptide to type B T cells was dramatically increased, but presentation of native Ag was negligible . Total levels of HLA‐DR and HLA‐DM were unaffected by exposure to S .…”