Sunday, December 7, 2014

When more is less: gut IgA prevents maturation of natural IgM immunity

This is a very interesting and thought-provoking study from journal Immunity. It focuses on immunobiology of gut associated follicular T helper (TFH) cells. This is a subset of helper T cells that is designed to provide necessary signals to germinal center (GC) B cells to produce high-affinity antibodies.

The authors study the role of P2rx7, a purinergic, ATP-activated receptor 7 on gut TFH function. Initially, the authors made an observation that P2rx7 is selectively and highly expressed on TFH. 
Interestingly, P2rx7-KO mice harbored increased number of TFH in peyer's patches (PP).

This increase in TFH cells in P2rx7-KO mice was cell-intrinsic since it was observed in CD3KO recipient mice adoptively transferred with 1:1 ratio of WT or P2rx7-KO PP T cells. 
Co-housing and co-(cross)-fostering experiments showed that effect of P2rx7 deficiency on TFH was independent of a any unique gut flora present in P2rx7-KO mice (though better experiments would have been to compare P2rx7-KO mice on Germ-Free (GF) background or test WT and P2rx7-KO mice from the same littermates).
Next, the authors found that greater presence of TFH in P2rx7-KO mice was linked to a reduced sensitivity of TFH to cell death in absence of P2rx7.
Additional experiments revealed that P2rx7-KO mice harbored more IgA producing cells in the gut (small intestine), but fewer IgM producing cells in the serum.
A scanning electron microscopic examination of small intestine revealed dramatic reduction of SFB colonization in P2rx7-KO mice.
Finally, series of in vivo experiments with cecal ligation and puncture (CLP) showed that P2rx7-KO mice were highly sensitive to death after sublethal CLP and they could be rescued with serum IgM injection from WT mice.
In summary, the data in this paper suggest that overzealous gut TFH function in P2rx7-KO mice contributes to the decline of the serum level of natural IgM and subsequent reduction of the host fitness in response to systemic inflammation.  

Some questions remains to be answered: 

(a) Why are gut TFH cells but not spleen or LN TFH cells sensitive to ATP? 

(b) Why gut IgA cannot compensate for serum IgM?

(c) If TCR signaling makes WT TFH refractory to ATP mediated cell death, does it mean that P2rx7-KO mice generate an excess of antigen non-specific TFH but not antigen-specific TFH compared to WT mice? In other word, does ATP controls antigen-(commensal)-specific TFH development?

David Usharauli

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