About

Work in the Bettini labs is focused on T cell biology. We ask questions related to T cell development and function in the context of autoimmunity, cancer, and intestinal homeostasis. We leverage basic immunology knowledge to develop new therapeutic approaches for treatment of autoimmunity and cancer.

Research topics

• Biology
• Immunology
• Medicine
• Cell biology
• Genetics
• Biochemistry
• Bioinformatics
• Endocrinology
• Chemistry
• Computational biology

Selected publications

• Flt3L-Derived Antigen-Presenting Cell Transfer in Neonatal NOD Mice Reduces the Incidence of Type 1 Diabetes

  Diabetes · 2025-11-06

  articleOpen accessSenior author

  Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive stages culminating in T-cell-mediated destruction of the β-cells at the islets of Langerhans. The immune mechanisms that initiate T1D are not fully resolved but likely involve an interaction between proinflammatory antigen-presenting cells (APCs) and autoreactive T cells that initiate immune infiltration and activation. Previous studies have tested the use of tolerogenic APCs in adult female NOD mice to delay or prevent T1D with only slight to intermediate success. Moreover, immune infiltration begins as early as age 4 weeks; therefore, targeting autoreactive T cells with tolerogenic APCs in adult mice may not impact later stages of diabetes. Thus, we hypothesize that the transfer of tolerogenic APCs at the neonatal stage prior to priming and immune infiltration will result in effective protection from autoimmunity. Our studies demonstrate that immature APCs travel to the pancreatic draining lymph nodes, alter the cytokine milieu in young mice, divert autoreactive CD4+ T cells to anergy, and drastically decrease proliferation and function of cytotoxic lymphocytes in adult prediabetic mice, leading to a significant reduction in the incidence of T1D. ARTICLE HIGHLIGHTS: Neonatal transfer of immature dendritic cell-enriched Flt3L splenocytes significantly reduces the incidence of type 1 diabetes in female NOD mice. Early time points are associated with accumulation of anergic T cells. In adult mice, there is a reduction in CD4 T helper 1 cells and reduced proliferation and perforin of CD8 T cells. Our work demonstrates how targeting the neonatal window of tolerance alters autoimmunity outcome.

  PublisherOA PDFDOI

• Flt3L-derived Antigen Presenting Cell transfer in neonatal NOD mice delays the incidence of Type 1

  2025-11-06

  articleOpen accessSenior author

  <p dir="ltr">Type 1 Diabetes (T1D) is an autoimmune disease characterized by progressive stages culminating in T cell mediated destruction of the b cells at the islets of Langerhans. The immune mechanisms that initiate T1D are not fully resolved but likely involve interaction between pro-inflammatory antigen presenting cells and autoreactive T cells that initiate immune infiltration and activation. Previous studies have tested the use of tolerogenic antigen presenting cells (APCs) in adult non-obese-diabetic (NOD) female mice to delay or prevent T1D with only slight to intermediate success. Moreover, immune infiltration begins as early as 4 weeks old, therefore targeting autoreactive T cells with tolerogenic APCs in adult mice may not impact late stages of diabetes. Thus, we hypothesize that the transfer of tolerogenic APCs at the neonatal stage prior to priming and immune infiltration will result in effective protection from autoimmunity. Our studies demonstrate that immature APCs travel to the pancreatic draining lymph nodes, alter the cytokine milieu in young mice, divert autoreactive CD4<sup>+</sup> T cells to anergy and drastically decrease proliferation and function of CTLs in adult pre-diabetic mice leading to a significant reduction in the incidence of T1D.</p>

  PublisherDOI

• Flt3L-derived Antigen Presenting Cell transfer in neonatal NOD mice delays the incidence of Type 1

  2025-11-06

  articleOpen accessSenior author

  <p dir="ltr">Type 1 Diabetes (T1D) is an autoimmune disease characterized by progressive stages culminating in T cell mediated destruction of the b cells at the islets of Langerhans. The immune mechanisms that initiate T1D are not fully resolved but likely involve interaction between pro-inflammatory antigen presenting cells and autoreactive T cells that initiate immune infiltration and activation. Previous studies have tested the use of tolerogenic antigen presenting cells (APCs) in adult non-obese-diabetic (NOD) female mice to delay or prevent T1D with only slight to intermediate success. Moreover, immune infiltration begins as early as 4 weeks old, therefore targeting autoreactive T cells with tolerogenic APCs in adult mice may not impact late stages of diabetes. Thus, we hypothesize that the transfer of tolerogenic APCs at the neonatal stage prior to priming and immune infiltration will result in effective protection from autoimmunity. Our studies demonstrate that immature APCs travel to the pancreatic draining lymph nodes, alter the cytokine milieu in young mice, divert autoreactive CD4<sup>+</sup> T cells to anergy and drastically decrease proliferation and function of CTLs in adult pre-diabetic mice leading to a significant reduction in the incidence of T1D.</p>

  PublisherDOI

• Blocking IL-17a Signaling Decreases Lung Inflammation and Improves Alveolarization in Experimental Bronchopulmonary Dysplasia

  American Journal Of Pathology · 2024-08-06 · 3 citations

  articleOpen access
  PublisherOA PDFDOI

• Autoimmune CD4 T cell exhaustion is counteracted by peripheral circulating T cell population with stem-like potential

  The Journal of Immunology · 2024-05-01

  article

  Abstract Stem-like antigen specific T cells serve as a reservoir for autoimmune CD8 T cell responses. However, it is unclear whether CD4 T cells depend on a similar population to counteract depletion through terminal differentiation and exhaustion. Single cell RNAseq and flow cytometric analysis of NOD islet-infiltrating T cells revealed the heterogeneity of CD4 cells, with subpopulations displaying features of exhaustion. Blockade of T cell entry with FTY720 reduced T cell numbers in the tissue, and protected NOD mice from diabetes. Moreover, islet CD4 T cells progressively lose TCF1 expression overtime. Transfer experiments and T cell tracking in photoconvertible NOD.KikGR mice showed peripheral circulating T cells with stem-like TCF1+ phenotype as an important source for autoimmune T cells. We observed that islet infiltrating CD62L+ naïve-like T cells include low affinity antigen specific cells, show activation of TCR regulated genes, and exhibit epigenetic signature distinct from lymph node bona fide naïve T cells. Similarly, BDC2.5 islet antigen specific T cells circulating in peripheral non-draining lymphoid organs exhibit phenotypic and epigenetic signature of pre-primed, but largely undifferentiated T cells. Collectively, our data indicates that autoimmune CD4 T cell persistence is sustained through continuous recruitment of new T cells from circulating non-differentiated stem-like compartment.

  PublisherDOI

• Supplementary Tables 1-2, Figures 1-11 from Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape

  2023-03-30

  supplementary-materialsOpen access

  <p>PDF file - 1.1MB</p>

  PublisherDOI

• Supplementary Tables 1-2, Figures 1-11 from Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape

  2023-03-30

  supplementary-materialsOpen access

  <p>PDF file - 1.1MB</p>

  PublisherOA PDFDOI

• The Amphiregulin/EGFR axis has limited contribution in controlling autoimmune diabetes

  Research Square · 2023-08-03 · 3 citations

  preprintOpen accessCorresponding

  Conventional immunosuppressive functions of CD4+Foxp3+ regulatory T cells (Tregs) in type 1 diabetes (T1D) pathogenesis have been well described, but whether Tregs have additional non-immunological functions supporting tissue homeostasis in pancreatic islets is unknown. Within the last decade novel tissue repair functions have been ascribed to Tregs. One function is production of the epidermal growth factor receptor (EGFR) ligand, amphiregulin, which promotes tissue repair in response to inflammatory or mechanical tissue injury. Whether such pathways are engaged during autoimmune diabetes and promote tissue repair is undetermined. Previously, we observed upregulation of amphiregulin at the transcriptional level was associated with functional Treg populations in the non-obese diabetic (NOD) mouse model of T1D. We postulated that amphiregulin promoted islet tissue repair and slowed the progression of diabetes in NOD mice. Here, we report that islet-infiltrating Tregs have increased capacity to produce amphiregulin and both Tregs and beta cells express EGFR. Moreover, we show that amphiregulin can directly modulate mediators of endoplasmic reticulum (ER) stress in beta cells. Despite this, NOD amphiregulin deficient mice showed no acceleration of spontaneous autoimmune diabetes. Taken together, the data suggest that the ability for amphiregulin to affect the progression of autoimmune diabetes is limited.

  PublisherOA PDFDOI

• Data from Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape

  2023-03-30

  preprintOpen access

  <div>Abstract<p>Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4<sup>+</sup> and CD8<sup>+</sup> T cells in three distinct transplantable tumors. Dual anti–LAG-3/anti–PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, <i>Lag3</i><sup>−/−</sup><i>Pdcd1</i><sup>−/−</sup> mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer. <i>Cancer Res; 72(4); 917–27. ©2011 AACR</i>.</p></div>

  PublisherDOI

• CD3ζ ITAM Diversity Determines Chimeric Antigen Receptor Signaling and Function

  The Journal of Immunology · 2023-05-01

  articleOpen accessSenior author

  Abstract One of the major challenges facing CD28-based CAR-T immunotherapy is a lack of long-term T-cell persistence in patients. CD28 CARs exhibit strong signaling patterns that result in an acute tumor-killing response. However, based on studies with the conventional TCR, strong signaling favors terminal differentiation of T-cells that get exhausted faster while weaker CAR signaling favors more stem-like memory T-cell states with longer persistence. Hence attenuation of CAR signaling strength is a viable strategy for long term survival of CD28-CAR T-cells. Previous work has suggested that reducing CD3 ITAM diversity to single ITAM sequences while keeping the number of ITAMs same, attenuates TCR signaling strength to different extents. Based on this, we have designed modified ITAM diversity restricted CD28 based anti-CD19 CARs with the goals of optimizing CAR signaling and studying the non-redundant signaling properties of the individual ITAMs in the context of CARs. Our approach is different from reducing ITAM multiplicity as there is evidence suggesting that ITAM numbers might be important for CAR sensitivity. We hypothesize that the individual ITAM non-redundancy and the reduction in ITAM diversity will allow for optimization of CAR T cell signaling and improve T-cell persistence while maintaining sensitivity to low ligand densities. We have observed that our modified CARs can kill CD19+ leukemia cells in vitro. We observe functional differences in terms of cytokine production, proliferation, AICD and exhaustion. We have also observed differences in signal strength based on ITAM usage. These observations support the non-redundancy of ITAM signaling and open the possibility of optimizing CAR persistence and function in patients.

  PublisherOA PDFDOI

Recent grants

• Self-Reactive T Cell Development in Type 1 Diabetes

  NIH · $158k · 2015–2017

• TCR PARAMETERS OF TREG FUNCTION IN AUTOIMMUNITY

  NIH · $1.9M · 2017–2023

• Parameters T-Cell Receptor avidity during thymic selection in autoimmune diabetes

  NIH · $269k · 2014–2017

• Self-Reactive T Cell Development in Type 1 Diabetes

  NIH · $1.9M · 2019–2024

• Biophysical parameters of self-reactive TCR engagement in T1D

  NIH · $2.7M · 2023–2028

Frequent coauthors

• Maria Bettini

  University of Utah

  89 shared

• Dario A.A. Vignali

  University of Pittsburgh

  41 shared

• Maran L. Sprouse

  Baylor College of Medicine

  38 shared

• Creg J. Workman

  University of Pittsburgh

  30 shared

• Peter Vogel

  30 shared

• Seng‐Ryong Woo

  29 shared

• Meghan E. Turnis

  St. Jude Children's Research Hospital

  29 shared

• David M. Gravano

  University of California, Merced

  29 shared

Labs

• Bettini labPI