Type 1 diabetes (T1D) is a T cell—mediated autoimmune disease driven by β cell-specific CD8 T cells. How autoreactive T cells arise and sustain disease remains unclear. Using the non-obese diabetic mouse model of T1D, we previously identified a stem-like CD8 T cell population in the pancreatic lymph node (pLN) which initiates and sustains β cell destruction: stem T cells (TSC) self-renew and continuously give rise to differentiated progeny (TDIFF) that migrate to the pancreas and kill β cells. Spatial positioning of somatic stem cells is critical for their maintenance, and that niche restricted signals (i.e., WNT and NOTCH) regulate the balance between self-renewal and differentiation. However, if and how T cell stemness is associated with distinct intranodal positioning in pLN, and whether interference in migration disrupts differentiation, is unknown.
We conducted (i) paired single-cell RNA- and ATAC-sequencing, (ii) adoptive T cell transfer studies, (iii) high-resolution imaging, (iv) CRISPR/Cas9 mediated gene editing of autoimmune T cells in pLN to identify the molecular and functional characteristics of TSC and TDIFF.
We discovered unique transcription factors and epigenetic programs governing autoimmune T cell stemness and differentiation. TSC and TDIFF express distinct chemokine receptors and integrins, suggesting that T cell stemness and differentiation are driven by intranodal positioning. Strikingly, WNT and NOTCH signaling were enriched in TSC, driving the expression of critical stem genes, thereby connecting T cell stemness to somatic stem cell biology. Pharmacological blockade and CRISPR/Cas9-mediated deletion of integrins and cell-cell interactions prevented autoimmune T cell differentiation and disease.
Our studies identify novel transcriptional regulators and niche-dependent signals that determine autoimmune T cell stemness and differentiation, opening novel therapeutic avenues for the prevention and treatment of T1D and other autoimmune diseases.
NIH F31DK141119, NIH R01AI173249, Juvenile Diabetes Research Foundation JDRF SRA-2023-1410-S-B, MSKCC Basic Research Innovation Award (BRIA), Hearst Foundation
Lymphocyte Differentiation and Peripheral Maintenance (LYM)
S. Miakicheva, Katrina M. Hawley, P. Zumbo et al.· Journal of Immunology· 0 citations
Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease where CD8 T cells eliminate insulin-producing β cells in the pancreatic islets. Yet, MHC class II haplotypes confer the greatest genetic risk for the development of T1D, suggesting a critical role for CD4 T cells. Employing the non-obese diabetic (NOD) mouse model, our lab identified in the pancreatic lymph node (pLN) a stem-like β cell-specific CD8 T cell pool required to initiate and sustain disease: pLN β cell-specific stem-CD8 T cells self-renew and continuously give rise to differentiated progenies which migrate to the pancreas (PA) and eliminate β cells; the pLN stem-CD8 T cell pool is absolutely required to sustain β cell destruction. Given the importance of autoimmune stem-CD8 T cells and the association of MHC class II in T1D pathogenesis, we wanted to understand the role of CD4 T cells in autoimmune CD8 T cell stemness and differentiation.
We employed the NOD model and longitudinally assessed the phenotypic and functional characteristics of β cell-specific CD4 T cells using flow cytometry, serial transplantation, CRISPR/Cas9-mediated gene editing, and transcriptomic studies.
Our studies reveal, for the first time, how CD4 T cells drive autoimmune CD8 T cell stemness, differentiation, and pathogenicity. We find β cell-specific CD4 T cells in pLN and PA reveal two distinct populations based on their expression of TCF1, a transcription factor critical for stemness and self-renewal. Functional studies identify pLN TCF1hi CD4 T cells as stem-T cell subset needed to drive the generation and maintenance of autoimmune stem-CD8 T cells in pLN, their differentiation into β cell-destroying cytotoxic effector cells, and ultimately T1D.
A unique population of β cell-specific CD4 T cells in pLN is critical for autoimmune CD8 T cell stemness, differentiation and disease. Identifying therapeutic strategies that target autoimmune stem-CD4 T cells could emerge as powerful approaches for the treatment of T1D.
NIH grant 1F31DK145180, NIH grant R01AI173249, Juvenile Diabetes Research Foundation grant JDRF SRA-2023-1410-S-B,
Basic Autoimmunity (BA)
Ian McBain, P. Zumbo, S. Miakicheva et al.· Journal of Immunology· 0 citations
To define mutation-specific lineage reversion and tumor initiation, Ptf1a-tdTomato mice and multiple KRAS mutants are implemented across several genetic, pharmacologic, and inflammatory perturbations in vivo to deciphering mutation-specific oncogenic trajectories and directing the implementation of KRAS-directed therapeutics.
A. Grimont, David Falvo, W. Sisso et al.· Developmental Cell· 1 citation
It is found that TSC in chronic infection harbor a LEF1+ TSC pool sharing the core stemness epigenetic and molecular program observed in autoimmune LEF1+ TSC, discovering LEF1 as the master regulator defining T cell stemness and identify novel targets for therapeutic intervention.
Katrina M. Hawley, S. Miakicheva, P. Zumbo et al.· Journal of Immunology· 0 citations
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