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Genetic alterations in indolent GI T-cell LPD
from naïve T cells into bifunctional mucosal Th1/2 cells, similar to those described in primary immune responses against parasites, which help dampen inflammation,49 or derive from Th1 or Th2 cells that have undergone cytokine-mediated reprogramming to acquire a Th1/Th2 phenotype, with concomitant production of Th1 and Th2 cytokines.50 The phenotypic shift from a Th1/Th2 to Th2 profile over time, observed in one CD4+ case, suggests lin- eage (and possibly functional) plasticity of at least a sub- set of ITLPD. The majority of the CD8+ cases and the CD4-/CD8- ITLPD displayed a Tc2 phenotype.51 Besides orchestrating diverse functions in CD4+ T-helper cells, GATA3 also regulates the activation, homeostasis, and cytolytic activity of CD8+ T cells.52 The significance of T- bet/GATA3 co-expression in CD8+ ITLPD is unknown. It must be pointed out that despite the reported concor- dance between the transcriptional and protein expression profiles of T-bet and GATA3 in certain T-cell lymphomas,27 the definitive lineage (and function) of neo- plastic T cells cannot be ascertained based on the expres- sion of single lineage-associated transcription factors. Cytokine profiling and in vitro functional studies are
awaited for confirmation of our observations. Contrary to observations in peripheral T-cell lymphoma, not other- wise specified,27,53,54 however, an inferior prognostic impact of GATA3 expression was not apparent in our series of ITLPD.
In conclusion, our study reveals considerable immunophenotypic and genetic heterogeneity of GI ITLPD. We describe recurrent and novel genetic abnor- malities in different immunophenotypic subtypes of GI ITLPD which implicate deregulated cytokine signaling and epigenetic alterations in disease pathogenesis. It is hoped that future unbiased interrogation of ITLPD genomes and transcriptomes as well as mechanistic stud- ies will help to clarify the cell of origin and the functional consequences of the underlying genetic aberrations in these rare disorders, opening the door for targeted, less toxic and more effective therapies.
Acknowledgments
We would like to thank Raymond Yeh, PhD, for designing the primers, analyzing Sanger sequencing results, and generating electropherogram images of the IL2 rearrangements.
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