Staff Scientist National Institutes of Health Bethesda, Maryland, United States
Disclosure(s):
Charles Anderson, PhD: No financial relationships to disclose
Introduction/Rationale: Lymphocytic variant hypereosinophilic syndrome (LHES) is an eosinophilic disorder characterized by phenotypically aberrant memory CD4+ T lymphocytes that secrete type 2 cytokines, with patients at an increased risk of progression to lymphoma. The most common aberrant phenotype, CD3loCD4+, is also seen in some types of T cell lymphoma, including angioimmunoblastic T cell lymphoma (AITL).
Methods: To increase our immunological understanding of LHES and its relationship to T cell lymphoma, we performed CITE-seq with VDJ sequencing on CD4+ T cells from 15 patients, 12 with LHES and 3 with angioimmunoblastic T cell lymphoma (AITL).
Results: Cell annotation and TCR clonotypic analysis confirmed hyperexpanded CD3lo clonal populations in all 15 patients and identified clonally expanded CD4+ regulatory T cells in LHES but not AITL. Clonal expansion of cytotoxic CD4+ T cells was also seen in some patients. CD3lo cells were comprised of a single expanded clone in 7 patients with LHES but were oligoclonal in the remaining patients. CD3lo cells in LHES showed increased expression of Th2 receptor genes involved in effector responses (PTGDR2, IL17RB, IL9R, IL5RA) with variable expression of Th2 cytokines. Strikingly, many subjects had prominent adhesion/tissue signatures (MXRA7, CLU, DNM3, SEMA5A, PDLIM1, CCR4, CCR8), indicative of tissue residence. Three LHES patients had a mixed Th2/IL9R phenotype and one patient had cytotoxic Th2 cells. Analyses of clones from AITL subjects revealed effector programs distinct from Th2 signaling, indicating a development pathway distinct from that in LHES.
Conclusion: In summary, LHES is characterized by clonal expansion of multiple CD4+ T cell lineages. The expression profile of CD3loCD4+ cells in LHES is consistent with a direct role for lymphocytes in LHES tissue pathology, beyond promoting eosinophilia. Further, RNA expression profiling distinguishes CD3lo T cells in LHES from those in AITL.
