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J Allergy Clin Immunol. 2008 Jan;121(1):57-63.e3. Epub 2007 Nov 5.

Epigenetic regulation of established human type 1 versus type 2 cytokine responses.

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Canadian Institute for Health Research, National Training Program in Allergy and Asthma Research, Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.



Multiple biologic factors influence maintenance of immunologic responsiveness. Here, we studied whether epigenetics has a regulatory function in maintaining pre-established T(H)1-like and T(H)2-like immunity in human beings.


We focused on delineating the role of endogenous histone deacetylase (HDAC) activity in regulating cytokine recall responses.


Using RT-PCR and ELISA, the effect of increasing cellular acetylation on T(H)1/T(H)2 cytokine expression was systematically examined in 58 children by inhibiting HDAC activity with trichostatin A.


Phytohemagglutinin activation selectively stimulates antigen-experienced CD45RO+ T cells, eliciting recall cytokine responses. Trichostatin A reduced HDAC activity by approximately 1/3. The resulting cellular hyperacetylation led to increased T(H)2-associated (IL-13, 139%; IL-5, 168%; P < .0001) and reduced T(H)1-associated recall responses (IFN-gamma, 76%; CXCL10, 47%; P < .0001). IL-2 and IL-10 production were reduced 25% to 55% (P < .0001). These alterations in T(H)2-associated and T(H)1-associated recall responses were associated with increased expression of Gata-3 and sphingosine kinase 1, a T(H)1-negative regulator, independent of T-bet expression. Overall, inhibition of endogenous HDAC activity shifted T(H)1:T(H)2 ratios by 3-fold to 8-fold (P < or = .0001), skewing recall responses toward a more T(H)2-like phenotype, independent of the stimulus used.


Endogenous HDAC activity plays a crucial role in maintaining the balance of pre-established T(H)1-like and T(H)2-like responses, inhibiting excessive T(H)2 immunity.

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