Tuesday, August 13, 2019

Do regulatory CD8+ T cells control autoreactive CD4+ T cells in the mouse model of human MS?

Recently journal Nature published a very thought-provoking study from Mark Davis' lab. In it, the authors have described the existence of a specialized population of CD8+ T cells that prevented auto-reactive CD4+ T cells from causing autoimmune brain inflammation (EAE) in mice, a laboratory model for human multiple sclerosis.

Let's analyze what the study shows. Both Fig. 1 and Fig. 2 are rather superfluous as they simply show either time kinetics of CD4+, CD8+ and γδ+ T cells responses in the blood or CNS following autoantigen immunization (Fig. 1) or frequency of TCR clonal  distribution based on TCR β or both γ and δ sequencing (Fig. 2). It is not clear what was the purpose of showing them within the paper itself.

Next, the authors tested the TCR specificities for expanded clones of CD4+ or CD8+ T cells. Four of these CD4+ TCRs expressed in human leukemia SKW αβ−/− cells yielded robust staining with a MOG35–55 I-Ab peptide–MHC tetramer. 
Curiously, out of nine TCRs from CD8+ T cell clones expressed in a mouse T cell hybridoma 58 αβ−/− cells, none of them get stimulated when co-cultured with bone-marrow-derived dendritic cells pulsed with myelin protein-derived peptides (total of 350 myelin peptides were tested). So, something else, besides myelin protein, was driving CD8+ T cell expansion.

To identify epitope specificity for TCRs from CD8+ T cells, the authors used H2-Db yeast-pMHC libraries. Six of the clonally expanded and one positive control CD8+ TCRs were used. Two, EAE6 and EAE7 TCRs showed robust tetramer staining but no matches were found in the mouse genome. They referred to these peptides identified in the peptide library screen the surrogate peptides (SPs).

Interestingly, the co-immunization of these SPs with myelin peptide inhibited the development of brain inflammation in mice. 

More importantly,  CD8+ T cells harvested from SPs-immunized mice but not control, naive mice, inhibited myelin-specific but not ovalbumin-specific CD4+  T cells in vitro. 

Moreover, only Ly49+ but not Ly49− fraction of CD8+CD44+CD122+ T cells from SPs-immunized donor mice showed inhibitory function both in vitro and in vivo. Of note, the application of the anti-Qa-1b antibody had no effect on the CD8 suppression of Myelin-specific CD4+ T cells. Here, the authors also tested CD8+ T cell reactivity to CFA (complete Freund’s adjuvant) or PTX (pertussis toxin) used in EAE immunization protocol and found that it did not increase Ly49+ fraction.

So, how can we summarize this paper? First, focus on γδ+ T cells here is extra and feels out of context. Second, no endogenous peptides were found that mimic SPs found in the library screen. Could it be microbiota-derived? The authors did not consider this possibility, it appears. Third, how SPs-specific Ly49+ CD8+ T cells inhibit myelin-specific CD4+ T cells? Not clear. It does appear highly specific to myelin-specific CD4+ T cells in the context of brain inflammation. But myelin-specific CD4+ T cells see myelin peptides but these CD8+ T cells do not seem to recognize them. Very confusing indeed. 
In general, the "memory-like" CD8+ T cells, such as Qa-1b-restricted population, has been known to inhibit immune response. This paper simply provides some new evidence in that direction. But it is not a novel idea or observation and without some novel mechanistic evidence I don't see how it could have landed in Nature's pages.  

posted by David Usharauli  

No comments:

Post a Comment