Dual TCR expressing T cells could drive autoimmunity

An article in Cell Host and Microbe (CHM) caught my attention. In proposed that dual TCR expressing T cells are responsible for autoimmune phenotype in K/BxN mice. 

K/BxN mice develop spontaneous arthritis thought to driven by Vβ6+ KRN T cells recognizing glucose-6-phosphate isomerase (GPI), the self-Ag presented by MHC class II A^g7 molecules. Ordinarily, it is thought that pathogen cross-reactive to self antigen, in this case GPI, could initiate autoimmune disease (theory of molecular mimicry).

However, recently the role of endogenous microbiota in driving autoimmune arthritis received new attention. Here, the authors showed segmented filamentous bacteria (SFB) was required to initiate autoimmune arthritis in K/BxN.

However, since SFB-derived peptide recognized by T cells required Vβ14+ TCR it was unclear how SFB was mediating autoimmunity against GPI recognized by completely different TCR made of Vβ6+ chain. Further analysis showed that some T cells in K/BxN express dual TCRs expressing both Vβ6+ and Vβ14+ chains. Indeed, sorted T cells expressing dual TCR, but not Vβ6+ chain alone, recognized SFB-derived peptide (A6).

In vivo, adoptive transfer of monoclonal KRN T cell population on RAG KO background that prevents expression of other Vβ or Vα chains (only expressing Vβ6+ KRN T cells), could not mediate arthritis in T cell-deficient host (harbor normal B cells also required for arthritis development). Of note, other paper in 1999 however found no difference in arthritis development between WT and RAG KO KRN T cells.

In summary, the authors think that first dual TCR T cells get activated by SFB-derived epitope via Vβ14+ TCR, indirectly prime Vβ6+ TCRs, on the same T cells, that then actually mediates autoimmunity against self antigen GPI. However, it is not clear from this study whether endogenous Vα chains could contribute to cross-reactivity between SFB and GPI when recombined with Vβ6+ or Vβ14+ chains in WT KRN T cells.

posted by David Usharauli



   

in vitro model to study commensal microbe-host interaction

Segmented filamentous bacteria (SFB) is a commensal gut microbe in laboratory mouse. Importantly, few years ago SFB was identified as microbe that could specifically drive TH₁₇ development in the mouse gut as well as induce general gut immune system maturation.

It is anaerobic microbe with no known in vitro growth conditions. However, to reduce laboratory animal suffering and unnecessary in vivo experimentation, it would be advantageous to be able to study SFB-host interactions in vitro.

This is exactly what the authors of the new paper published in journal Nature had tried to accomplish (this paper was under review for 1 year). The authors were able to develop in vitro SFB-mammalian cell co-culture that yielded functional colonies of SFB.

The authors showed that in vitro culture of SFB required presence of live cells (both human (caco-2/TC7 line) or mouse cells (mICcl2 line) were tested) and iron.

Importantly, in vitro derived SFB could colonize germ-free mice and induce secretory IgA and  TH₁₇ development.

The authors showed that in vitro derived SFB induced gene expression profile in host cells in an in vitro assay that mimicked in vivo observations.

In summary, I hope this type of research advances would contribute not to just general increase of our knowledge of commensal-host interaction, but also would indirectly improve laboratory animal welfare by reducing their use in the lethal, terminal experimentation.

David Usharauli