Thursday, January 15, 2015

Christmas tree theory of T cell functional polarization

Pathogens capable of productive infection of immune-competent host (1) can target one or more tissues or (2) different pathogens can target the same tissue

Conversely, immune system, in theory, should be able to deploy pathogen-tailored immune response for efficient control

However, for a host, there is an additional cost when deploying pathogen-tailored immune response: it may inflict potentially severe, bystander self-wounding, if class of immune response is too harsh for local tissue. 

So, there is always a delicate balance between anti-pathogen response and tissue-specific immune response restriction, "self-censorship". As Melvin Cohn, one of the last surviving immunology theoretician opined "Lighting up the immune response like a Christmas tree would be ineffective".

Still, immunology is a science and science since the days of Galileo Galilei required robust experimental proof to accept or reject a proposed theory.

The following paper from journal Science examined the specificity and functional polarization of human memory CD4 T cell subsets specific for (1) C. albicans (extracellular fungus) and M. tuberculosis (intracellular bacteria) and (3) protein, Tetanus toxoid (TT vaccine). [senior author: Federica Sallusto; first author: Simone Becattini].

The authors have sorted human peripheral blood derived TH1, TH2, TH17 and non-conventional TH1* CD4 T cells based on surface chemokine receptor profile and stimulated them in vitro with autologous monocytes and C. albicans

The authors observed that despite different frequencies of ex-vivo expanded C. albicans-specific TH1, TH2, TH17 and non-conventional TH1* CD4 T cells (see above), all 4 subsets contained comparable number of clonotypes (based on TCR-beta analysis). Q: why such waste?

Interestingly, TCR-beta analysis indicated that many C. albicans-specific clonotypes were shared between these 4 CD4 T cell subsets, implying that they were related.

Similar results were obtained when analysed protein, TT-specific clonotypes.

Limited analysis of both TCR-beta and TCR-alpha chains showed that some of shared clonotypes were actually identical, sister clones.

In summary, the results indicates that single CD4 T cells can acquire multiple fates. More broader interpretation of these results imply that immune system may indeed produce diverse T cell subsets (lighting up of Christmas tree) against given pathogen and then expands those subsets capable of controlling the infection.  

Of course, we do not know whether sister clones were actually derived from the same identical mother clone. It may be that one sister clone was primed in gut tissue and another sister clone was primed in skin tissue (where ever it first encountered non-self antigen). Also, we still don't know the role, if any, of each subsets specific for a given infection.    

David Usharauli  

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