J. Michael Stolley Laboratory

Research

Overview

Adaptive immune cells chronicle an individual’s infections past and afford protection from reinfection. Such ‘immunological memory’ is achieved through a division of labor. Whereas B cells secrete antibodies - soluble proteins which neutralize pathogens at a distance - the effector functions of T cells are contact-dependent. Therefore, if you are a T cell, location matters. Mucosal tissues including the intestine, lungs, and urogenital tract represent primary sites of pathogen transmission. T cell Immunosurveillance within these barrier tissues is crucial for maintaining the health of the organism.  Resident memory T cells (TRM) are a subset of memory T cells that durably surveil these (and other) frontline tissues without recirculating. Upon pathogen re-encounter, TRM rapidly reactivate to orchestrate local collaborative immune responses. However, the differentiation state of TRM is influenced by instructive cues that vary from one anatomic location to another. While the tissue-specific functions of TRM have begun to be well characterized in many locations, an understanding of the ontogeny, distribution, and functional implications of TRM in the oral mucosa and periodontium remains practically nonexistent. A more thorough understanding of how TRM form and function in the mouth will allow us to contextualize their role in oral health and disease and may uncover new therapeutic targets to harness or inhibit their immunostimulatory potential.  

Tools and Lab Expertise (Stolley et al., Journal of Experimental Medicine, 2023)

· Oral tissue isolation

· Oral TRM generation using Viral-Prime, Epitope-Pull (VPEP)

· Oral TRM reactivation

· Oral TRM depletion using toxin conjugated antibodies

· Ligature induced periodontitis

· Oral tissue histology

· Oral infections

· Murine saliva collection 

Areas of Interest  

Oral-resident antiviral T cell responses in periodontitis Periodontitis is the world’s most common chronic inflammatory condition. Characterized by unresolved gingival inflammation, CD4+ T helper cells are considered major drivers of disease in response to commensal and pathogenic oral microorganisms. Whether antiviral TRM can impact periodontitis progression and severity remains unknown. The oral mucosa is vulnerable to infection by viruses including members of the Herpesviridae family, human papilloma virus (HPV), Coxsackie viruses, and coronaviruses; many of which are transmissible through an oral route. We previously identified dense accumulations of oral TRM populating mouse gingiva where their local reactivation induced discernable inflammation and transcriptional induction of genes etiologic in periodontitis (Stolley et al., 2023 & In Preparation). We hypothesize that viral triggering of gingival TRM represents an overlooked aspect of the etiopathology of periodontal disease.  

Impact of oral-resident T cell reactivation on gustation (taste) Oral infection and inflammation can impact taste perception. Previous work identified TRM commonly surveil taste buds of the soft palate and tongue (Stolley et al., 2023). Taste buds encompass an assemblage of 50–100 individual taste receptor cells (TRCs) that sense and transduce signals upon receptor ligation of proteins, carbohydrates, salt, acids, and bitter compounds in food. In TRCs, taste receptors localize to gustatory hairs; projections in the TRC plasma membrane, which traverse the taste pore into the mouth. This intentional breach in the oral epithelium may represent an access point for viruses infecting the mouth, and therefore TRM immunosurveillance of taste buds may reinforce protection at this particularly vulnerable mucosal location. We hypothesize that reactivation of taste bud adjacent TRM will impact gustation (taste) through mechanisms including TRC gene expression changes, synaptic signaling, and TRC death.

Co-opting the immunostimulatory potential of oral TRM against oral cancer Oral cancer currently represents the sixth most prevalent cancer globally, with HPV and alcohol/tobacco use representing major etiological factors. The incidence of oral cancer is increasing and is forecasted to claim ∼500,000 lives per year by 2030. Removal of oral cancerous lesions can cause severe and permanent disfigurement and impact basic life functions. Alternative treatment options are needed. We previously reported that oral TRM can be ‘tricked’ into mounting a local antiviral response by swabbing the oral surfaces with virus-mimicking peptides, and that this manifests the formation of inflammatory aggregates and induction of several antitumor genes (Stolley et al., 2023). Antiviral memory T cells infiltrate human solid tumors, and mouse studies have demonstrated the anti-tumor effects of reactivating antiviral T cells within tumors (Rosato et al., 2019). We are similarly interested in co-opting the proinflammatory functions of oral TRM against oral cancer. Such an approach may represent a particularly tractable therapy given the accessibility of the oral mucosa for antiviral peptide swabbing.  

Oral TRM reactivation and saliva production/composition Saliva initiates alimentation, lubricates oral structures, buffers enamel-degrading acids, and harbors antimicrobial proteins and mucosal antibodies. Leukocyte infiltration within minor salivary glands is often diagnostic of Sjogren’s syndrome in human labial mucosa biopsies. We previously reported TRM infiltrating minor salivary glands and ducts throughout the mouth (Stolley et al., 2023), where their local reactivation precipitated minor salivary gland inflammation. Moreover, oral TRM reactivation within the buccal mucosa (which harbors many secretory structures) resulted in the transcriptional upregulation of metal scavenging and complement activation genes encoding proteins present in saliva. That saliva output and the abundance of antimicrobial proteins contained therein may be under the influence of mouth-resident T cells would have implications for the oral microbiota and diseases impacting saliva production.  

Documenting T cell behavior in living mucosal epithelium There is a paucity of in vivo data for mucosal T cell motility. Its ease-of-access, diverse tissue architectures, and varying degrees of epithelial stratification make the mouth an attractive yet uncharted location for addressing fundamental questions regarding the immunosurveillance properties of TRM using imaging techniques including intravital microscopy.                   

Selected Publications

Publications (ordered by most recent)

Stolley JM, Scott MC, O’Flanagan SD, Künzli M, Matson CA, Weyu E, Langlois RA,  Vezys V, Masopust D. Cutting Edge: First Lung Infection Permanently Enlarges Lymph Nodes and Enhances New T Cell Responses . J Immunol 2024; ji2400010

Stolley JM, Scott MC, Joag V, Dale AJ, Johnson TS, Saavedra F, Gavil NV, Lotfi-Emran S, Soerens AG, Weyu E, Pierson M, Herzberg MC, Zhang N, Vezys V, Masopust D. Depleting CD103+ resident memory T cells in vivo reveals immunostimulatory functions in oral mucosa. Journal of Experimental Medicine. 10.1084/jem.20221853  

Fiege JK, Block KE, Pierson M, Nanda H, Shepherd FK, Mickelson C, Stolley JM, Matchett WE, Wijeyesinghe S, Meyerholz DK, Vezys V, Shen SS, Hamilton SE, Masopust D, Langlois RA. (2021). Mice with diverse microbial exposure histories as a model for preclinical vaccine testing. Cell Host and Microbe. S1931-3128(21)00463-7  

Matchett WE**, Joag V**, Stolley JM**, Shepherd FK, Quarnstrom CF, Mickelson CK, Wijeyesinghe S, Soerens AG, Becker S, Thiede JM, Weyu E, Flanagan S, Walter JA, Vu M, Menachery VD, Bold TB, Vezys V, Jenkins MK, Langlois RA, Masopust D. (2021). Nucleocapsid vaccine elicits spike-independent SARS-CoV-2 protective immunity. Journal of Immunology. 207 (2) 376-379 **Co-first Author Journal of Immunology top 20 most-read articles of 2021  

Wijeyesinghe S, Beura L, Pierson MJ, Stolley JM, Adam OA, Ruscher R, Steinard EM, Rosato PC, Vesyz V, Masopust D. (2021). Expansible residence decentralizes immune homeostasis. Nature. 592, 457–462  

Joag V, Wijeyesinghe S, Stolley JM, Quarnstrom CF, Dileepan T, Soerens AG, Sangala JA, O'Flanagan SD, Gavil NV, Hong SW, Bhela S, Gangadhara S, Weyu E, Matchett WE, Thiede J, Krishna V, Cheeran MC, Bold TD, Amara R, Southern P, Hart GT, Schifanella L, Vezys V, Jenkins MK, Langlois RA, Masopust D. (2021). Cutting Edge: Mouse SARS-CoV-2 Epitope Reveals Infection and Vaccine-Elicited CD8 T Cell Responses. Journal of Immunology. doi: 10.4049/jimmunol.2001400 Journal of Immunology top 20 most-read articles of 2021  

Stolley JM, Johnston TS, Soerens AG, Beura LK, Rosato PC, Joag V, Wijeyesinghe SP, Langlois RA, Osum KC, Mitchell JS, Masopust D. (2020). Retrograde migration supplies resident memory T cells to lung draining LN after influenza infection. Journal of Experimental Medicine. 217 (8): e20192197  

Rosato PC, Wijeyesinghe, SP, Stolley JM, Nelson EC, Davis RL, Manlove, LS, Pennell, CA, Blazar BR, Chen CC, Geller MA, Vezys V, Masopust D. (2019). Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy. Nature Communication. 10(1):567  

Rosato PC, Wijeyesinghe SP, Stolley JM, Masopust D. (2019). Integrating resident memory into T cell differentiation models. Current Opinions in Immunology. 63:35-42  

Stolley JM, Masopust D. (2017). Research Highlight: Tissue resident memory T cells live off the fat of the land.  Cell Research. 27(7): 847–48  

Stolley JM, Campbell DJ. (2016). A 33D1+ DC / auto-reactive CD4+ T cell circuit maintains Il-2 dependent regulatory T cells in the spleen.  Journal of Immunology. 197(7):2635-45  

Smigiel KS, Srivastava S, Stolley JM, Campbell DJ. (2014). Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation. Immunological Reviews. 259(1):40-59  

Stolley JM, Gong D, Farley K, Zhao P, Cooley J, Crouch EC, Benarafa C, Remold-O'Donnell E. (2012). Increased surfactant protein D fails to improve bacterial clearance and inflammation in serpinB1-/- mice. American Journal of Respiratory Cell and Molecular Biology. 47(6):792-9  

Farley K, Stolley JM, Zhao P, Cooley J, Remold-O'Donnell E. (2012). A serpinB1 regulatory mechanism is essential for restricting neutrophil extracellular trap generation. Journal of Immunology.189(9):4574-81  

Benarafa C, LeCuyer TE, Baumann M, Stolley JM, Cremona TP, Remold-O'Donnell E. (2011). SerpinB1 protects the mature neutrophil reserve in the bone marrow. Journal of Leukocyte Biology. 90(1):21-9