Jonathan A. Harton, PhD
Areas of Study
Molecular regulation of immune responses
- University of Iowa1995PhD
- Eastern College1987BS
Research in the Harton lab is focused on understanding the molecular regulation of immune responses. A broad array of molecular, cellular, and in vivo approaches are employed to address questions relevant to innate immunity, inflammation, and cancer. Current work in the laboratory focuses on the molecular and cellular basis of the innate immune response to Francisella tularensis (a potential biological warfare agent), activation of the NLRP3 inflammasome, and regulation of inflammatory signal pathways by Pyrin-only proteins (POPs). Additional interests include the function and role of the master transcriptional regulator of MHC class II genes, CIITA in cancer immunology and MHC class II signaling.
Immunobiology of F. tularensis
Dr. Harton currently leads subproject 2 of the Francisella program project grant. F. tularensis (Ft) is a highly virulent pulmonary pathogen that causes death of an infected, untreated host within several days. Invading Ft is detected by a limited array of host receptors that include TLR2, AIM2, and NLRP3 which promote inflammatory cytokines responses including TNFα, IL-1β, and IL-6 important for host protection. Although mice and mouse macrophages infected with the Ft-related bacterial strain F. novicida rely exclusively upon AIM2 for an IL-1β inflammasome response, human macrophages utilize both AIM2 and NLRP3 (Atianand et al 2011). However, mice infected with Ft-LVS (the human live vaccine strain) or Schu S4 (a highly virulent pathogenic strain) fail to mount a successful innate immune response and die. Although Ft replicates to high numbers in infected mice, high bacterial loads are not responsible for death of the host. Instead, an immature and ineffective cellular inflammatory response predominates in the lungs of mice infected with sufficient numbers of Ft bacteria and contributes to lung damage, loss of pulmonary function, and death (Periasamy et al In Review). The cellular and molecular basis for the appearance of these cells and how they contribute to host tissue damage and death are questions being presently pursued.
The NLRP3 Inflammasome
While working with Dr. Jenny Ting to understand the function of CIITA, Dr. Harton was instrumental in the discovery of the NLR gene family (Harton et al. 2002). The proteins encoded by these genes have roles in transcriptional regulation, development, and pathogen sensing. Multiprotein inflammasome complexes can be assembled by various NLRs and some non-NLR proteins, but all of these activate caspase-1, an aspartic acid protease key to the proteolytic maturation of IL-1β, an important inflammatory cytokine, and IL-18, a cytokine important for promoting IFNγ production by T and NK cells. The NLRP3 inflammasome complex is the best studied owing to its central role in driving the IL-1β response to a wide range of infectious, environmental, and 'sterile' host molecules, including Francisella (Atianand et al 2011). Ongoing studies seek to understand the molecular basis for Ft activation of the NLRP3 inflammasome and the in vivo role of NLRP3 during pulmonary tularemia.
Pyrin-Only Protein 2 (POP2)
A homotypic Pyrin:Pyrin domain interaction mediates the formation of most inflammasomes. POP2 is a primate-restricted protein (Atianand et al 2011) comprised solely of a Pyrin domain which acts as an endogenous competitive inhibitor of the NLRP3 inflammasome (Bedoya et al 2007). POP2 prevents the Pyrin:Pyrin interaction of NLRP3 with the adaptor protein ASC and thus serves to regulate downstream IL-1β and IL-18 processing activity. POP2 also inhibits the transcriptional activity of NF-kB, a key transcription factor important for expression of various proteins important for inflammation, cell cycle control, and other cellular processes (click here for a review). Inhibition of either NF-kB or the NLRP3 inflammasome requires only the first 19 amino acids, but the requirements for each appear distinct (Atianand and Harton 2011). The dual regulatory role of POP2 likely important in multiple human inflammatory conditions such as
rheumatoid arthritis, type II diabetes, and atherosclerosis.
CIITA and Cancer Immunology
The transcriptional control of class II MHC genes is important for antigen presentation and tumor recognition. At the molecular level we are interested in dissecting the ability of a transcriptional regulator, CIITA, to differentially regulate HLA-DR and its chaperones invariant chain and HLA-DM. CIITA's influence on MHC II transcription is highly regulated and involves CIITA's GTP-binding domain (Harton et al 1999; Bewry et al 2007), leucine rich repeats (Harton et al 2000), phosphorylation (Li et al 2001; Greer et al 2004, Xu et al 2008) ubiquitination, and interactions with a host of transcription factors (click here for a review). We hypothesize that differences in regulation of CIITA-responsive genes influences antigen presentation. This is important for clinical problems ranging from arthritis to multiple sclerosis and from transplant biology to cancer. While assessing the mechanisms of CIITA's transactivator function at the molecular level, at the level of disease, we are employing molecular tools towards understanding how class II MHC contributes to tumor elimination, equilibrium and escape in the mouse models of melanoma and breast cancer.
MHC Class II Signaling
In addition to the antigen presentation functions of class II MHC, these molecules also deliver activation signals to antigen presenting cells. In the case of B cells, MHC class II signals appear to be important for cell survival, growth, and differentiation to antibody secreting cells. Work in this area is a longstanding interest and is the subject of ongoing collaboration with Dr. James Drake.
Nagar A, DeMarco RA, Harton JA. 2019 Inflammasome and Caspase-1 Activity Characterization and Evaluation: An Imaging Flow Cytometer-Based Detection and Assessment of Inflammasome Specks and Caspase-1 Activation. Journal of Immunology. 202(3):1003-1015.
Periasamy S, Harton JA. 2018 Interleukin 1α Promotes Pathogenic Immature Myeloid Cells and IL-1β Favors Protective Mature Myeloid Cells During Acute Lung Infection. Journal of Infectious Diseases. 217:1481-1490.
Periasamy S., Porter K.A., Atianand M.K., Le H.T., Earley S., Duffy E.B.,Haller M.C., Chin H., Harton J.A. 2017 Pyrin-only protein 2 limits inflammation but improves protection against bacteria. Nature Communications 8:15564.
View Jonathan A. Harton's articles on the National Institute of Health's PubMed website.