Monday, July 6, 2015

Determinants of T cell exhaustion during chronic viral infection and autoimmunity

Typically when we think about ordinary immune response, we imagine several finite steps involving T and B cells, such as antigen recognition and initiation of antigen-specific clonal expansion, control of antigenic spread and elimination of infected cells and finally return to quiescent state and memory establishment.    
This scenario represents what ordinary is called immune response to transient (acute) antigenic stimulation. However, how does host immune system respond to persistent (chronic) antigenic stimulation, for example, chronic viral presence (HIV, HVB, HCV, Malaria, TB) or autoimmune disease (self-antigens)? Are the mechanisms that control immune response similarly activated during acute or chronic antigenic presence?

As you can see many infectious diseases with no effective vaccines fall exactly in the category of chronic infections (HIV, HBV, HCV, Malaria, TB). This is not a random outcome. There should be some biological or immunological underpinning to account for our failure to develop such vaccines. 

This new paper in journal Nature provided some additional results that may help us to better understand mechanisms controlling chronic immune responses. To tell the truth, it is quite difficult-to-digest article with lot of large data set analyses. The paper was under review for more than 1 year and its main finding regarding molecule KAT2B isn't even mention in their abstract. Strange. So we just need to assume that their analyses are done correctly and are statistically valid.

In this paper the authors tried to correlate CD8 T cell exhaustion phenotype with the clinical outcome (flare-free survival) of patients suffering from various autoimmune diseases. Murine chronic LCMV infection-associated CD8 T cell exhaustion phenotype was used as a reference. 

First, the authors noticed that unlike coordinated up-regulation of several inhibitory receptors during murine chronic LCMV infection, CD8 T cell phenotype from patients with autoimmune diseases displayed distinct disease-selective up-regulation of exhaustion-associated inhibitory receptors.

Interestingly, for each patient with autoimmune diseases, CD8 T cell exhaustion phenotype correlated with a favorable prognosis.


Next, in vitro experiments showed that fine balance between incoming co-stimulatory (e.g. CD2) and co-inhibitory (e.g. PD-L1) signals may determine exhaustion phenotype of CD8 T cells during persistent antigenic stimulation (one caveat: anti-CD3, anti-CD28 or anti-CD2 antibody stimulation are not physiological mode of activation, at all).


Finally, the authors showed that level of expression of KAT2B (top-ranked CD4 T cell co-stimulation candidate) could predict (1) favorable response during chronic viral infection and/or positive host response to vaccination, and (2) poor prognosis during autoimmune diseases.


In summary, these results indicate that treatment of chronic viral infection and chronic autoimmune diseases may require activation of opposite receptors.

David Usharauli



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