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Thursday, May 2, 2013

Mechanisms of T cell plasticity

Continuing with the topic of T helper cell “shapeshifting,” Hirahara et al. report on the complexity of environmental determinants and epigenetic factors that orchestrate T helper cell plastic responses (Journal of Allergy and Clinical Immunology 2013; 131(5):1276-1287). 

The authors discuss the regulatory and metabolic factors that affect the plastic capabilities of helper T cells.  Beginning with an excellent overview of the current taxonomy of Th cells, Hirahara et al. reviews the current understanding of CD4 T cell fate and their homeostatic interactions within T helper cell lineages. 

Further discussion addresses the idea of “signature” transcription factors and cytokine production in T cell lineages.  The authors question the accuracy and usefulness of this static characterization in light of the accumulating knowledge of T helper cell capacity for expression of multiple transcription factors and cross-family cytokines under the influence of different pathological contexts.   The complexity and variable expression of “master” transcription regulators is covered, in particular the STAT family of binding proteins. 

Hirahara et al. go on to discuss the transcription factor “orchestra” that permits the observed plasticity in response to different environmental conditions.  Transcription, epigenetic, and metabolic systems are discussed, with particular elaboration on those elements that are responsible for the accessibility of genes that can be transcribed.  Discussion includes active and silent histone modifiers, methylation, and “enhancers” found in junk DNA that are now being discovered as critical to gene expression. 

The authors conclude noting that future therapeutic approaches could possibly manipulate “good” CD4 T cell phenotypes to persist, while diminishing “bad” phenotypes.  Importantly, they point out that existing technologies may provide the tools necessary to accomplish this, but must be re-evaluated for their impact on factors that promote helper T cell plasticity. 

Chameleon T cells

Lloyd and Saglani present us with a new perspective on T cells as major players in asthma genesis this month (Journal of Allergy and Clinical Immunology 2013; 131(5):1267-1274). They discuss the classic Th2 model of asthma, and then begin to probe the inconsistencies that have arisen around this paradigm in light of current research and new therapeutics.

Lloyd and Saglani focus on current knowledge of the heterogeneity of asthma phenotypes, the lung epithelium interface, and the less than expected efficacy of new, Th2-targeted therapies to frame their discussions about the various types of effector T cell subsets including classic Th2 cells, Th17 and -22 cells, T regulatory cells, and the novel Th9 subset. The authors emphasize, where relevant, that T cell cytokines are now known to be associated with non-immune cell sources, such as the lung epithelium, and that is an important predicator of effector response. In fact, many T cell-related cytokines have both positive and negative modulating effects that are dependent on the cell type that produced them.

The authors review T cell plasticity as demonstrated in current mechanistic findings. For example, a novel T cell that expresses both GATA 3 and RORgt and secretes both Th2 and Th17 cytokines has recently been reported. This cell line elicited an augmented and more diverse inflammatory response in the lung. They also note that T cells can express more than one transcription factor and that it may be related to the environment within which the response is generated.

The critical role of the lung epithelium and its interactions with allergens and pathogens is highlighted, noting its primary role in initiating and orchestrating the sensitivity response. Further, Lloyd and Saglani comment that the characteristics of a response are variable and are determined by genetic environment and the cell that are the source of the cytokines. They point out that exogenous environmental conditions, such as smoke and pollution, also impact the characterization of the response.

Lloyd and Saglani conclude urging the development of more sophisticated methods for characterizing asthma response phenotypes in order to design more effective interventions. They point out that simple categorization of cell function and cytokine profile is misleading with regard to appropriate therapies, citing the mepolizumab clinical trial as an example. The authors suggest that manipulation of T cell fate and function, rather than blockade of their downstream cytokine products, should be explored as therapeutic alternatives.