Abstract
“If I have seen further, it is by standing on the shoulders of giants”.
—Sir Isaac Newton
I
It was in this nurturing environment that diversity in science was not only tolerated but also promoted and cherished and that younger scientists from all across the globe interacted with and learned from world-class scientists, some of whom were icons and giants of their respective fields. Dr. Young was one such individual who was internationally known for his studies in the realm of cytokine biology with a particular focus of IFN-γ.
Although Howard's home base was at the Frederick campus of the National Cancer Institute (NCI), I took every possible opportunity to attend his lectures and strike up a conversation to be on the receiving end of his infectious enthusiasm for breakthrough discoveries. When my abstract on the subject of CD8+ T cell responses to vaccinia virus was chosen for a brief podium presentation at a session cochaired by Howard during an NIH annual immunology retreat, I was over the moon. To this date, I have kept Howard's invitation e-mail for my viewing pleasure from time to time, especially when I feel nostalgic about my good old NIH days.
Howard has made significant contributions to our understanding of IFN responses in antitumor immunity, autoimmunity, chronic inflammatory disorders, and other conditions. The tools and models he has generated over the years, which he has generously shared with others, have helped answer many pressing questions regarding IFN-γ regulatory networks in health and disease. For instance, Howard's team created an elegant “designer” mouse model in which the adenylate–uridylate (AU)-rich element in the 3′ untranslated region of the IFN-γ mRNA is replaced by random nucleotides. These mice exhibit sustained IFN-γ expression, which has potential implications for aplastic anemia (Lin et al, 2014), systemic lupus erythematosus (Hodge et al, 2014), primary biliary cholangitis (Bae et al, 2016), and chronic inflammation associated with autoimmunity and gut dysbiosis (Bae et al, 2020).
Many of Howard's findings, observations, interpretations and ideas vis-à-vis IFN-γ gene expression, signaling, functions, and applications, along with others’, are articulated in the review articles he has produced (Burke and Young, 2019; Khabar and Young, 2007; Miller et al, 2009; Savan et al, 2009; Young, 1996; Young and Bream, 2007; Young and Ghosh, 1997; Young and Hardy, 1995). Some of the older articles among these reviews are invaluable resources for many of us who are interested in learning about the history of immunological studies on IFNs.
Howard was elected as a Fellow into the American Academy of Microbiology in 2000 and also served as Vice President and President of the International Society for Interferon & Cytokine Research (ISICR) (2002–2005) among other leadership roles and responsibilities. Equally important, if not more, Howard has always stood out as an exemplary mentor to many investigators, women and men, junior and established (I have begun to dislike the term “senior investigator” since I recently joined the club), who relied on his unconditional support, breadth of knowledge, and wealth of wisdom for their career progress.
It is therefore not surprising that Howard has received the NIH Director's Award for Mentoring in 2000, the first time this prestigious award was introduced, and twice more in 2006 and 2018. Howard's mentorship endeavors and qualities have also earned him the 2019 Mentoring Award from the Women Scientists Advisors (WSA), a group that promotes career development for women in science within the NCI, and the inaugural International Cytokine & Interferon Society (ICIS) Mentorship Award in 2021, among other distinctions. Howard was a champion of equity, diversity, and inclusiveness long before this important concept became popular and somewhat fashionable.
As a first-generation immigrant of Iranian descent who has called Canada home since 1996, I had quickly developed a skill to identify altruistic mentors who believe that science knows no borders and who promote junior researchers regardless of where they come from. It is noteworthy that my postdoctoral studies at the NIH had begun shortly after the tragic events of September 11, 2001, which had made the trainees of Middle Eastern origin live and work under a cloud of suspicion. I myself had to meet a requirement to report to a Homeland Security office in Baltimore for fingerprinting once every few months. Justifiable or not, such requirements had taken a toll on my emotional health and research productivity. However, I always took solace in knowing that I was surrounded by caring and compassionate scientists within the NIH community of scholars, including Howard.
I maintained a mentor–mentee relationship with Howard after I left the NIH to launch my independent research program at Western University in London, Ontario. I also knew whom I could turn to for advice whenever we were puzzled by difficult-to-explain findings arising from our studies on inflammatory responses and “cytokine storms”.
Our first formal collaboration came to fruition following a serendipitous observation by Peter Szabo, one of my former doctoral trainees (now at Columbia University), who was working on toxic shock syndrome (TSS). TSS is caused by staphylococcal and streptococcal exotoxins known as superantigens (SAgs), which bind simultaneously to the exterior surface of major histocompatibility complex (MHC) class II molecules (Dellabona et al, 1990) and select T cell receptor Vβ chains (White et al, 1989). This results in massive T cell proliferation, rapid cytokine production, and a state of hyperinflammation, which may lead to tissue damage, vital organ failure, and death (Lappin and Ferguson, 2009; Tuffs et al, 2018).
Therefore, there is an unmet need to identify the key players of the storm's initial wave for possible therapeutic interventions. Peter used human leukocyte antigen-DR4-transgenic mice and human cell culture systems to investigate inflammatory responses to staphylococcal enterotoxin B (SEB) among other SAgs. SEB is a major culprit of nonmenstrual TSS and food poisoning, and is considered a “category B bioterrorism” agent (Borchardt et al, 2006). Peter had discovered that exposure to SEB results in robust interleukin (IL)-17A production in in vitro and in vivo settings (Szabo et al, 2017a). Intriguingly, in human peripheral blood mononuclear cell cultures exposed to SEB, IL-17A mRNA expression was rapidly upregulated and gradually declined. However, the IL-17A protein continued to accumulate in culture. This was unlike IFN-γ whose mRNA and protein expression kinetics followed a similar pattern.
Howard provided us with a few testable hypotheses, including differential cytokine mRNA stability/degradation, to explain this phenomenon, and Peter was indeed elated to find that IL-17A transcripts were remarkably stable, much more so than those encoding IFN-γ. With Howard's critical input, we went on to identify an infrequent subpopulation of effector memory T lymphocytes, which we dubbed “TEM-17” cells, as the primary source of IL-17A in our experimental systems. These TEM-17 cells were enriched within the intestinal epithelium and among the lamina propria lymphocytes in our humanized mouse model. Finally, in vivo neutralization of IL-17A could ameliorate hepatic and intestinal tissue injuries and reduce the mortality rate.
Collectively, the above findings, which were featured in the “In This Issue” section of The Journal of Immunology and also through the Faculty of 1000 platform, revealed a pathogenic, rather than protective, role for IL-17A in the context of Gram-positive bacterial infections. They also prompted us to propose that the IL-17-IL-17R axis constitutes an attractive target in the management of SAg-mediated illnesses (Szabo et al, 2017a).
Mainstream T lymphocytes are not the only T cells that are targeted by bacterial SAgs. Jacqueline Hayworth, a former Master's student (now a family physician), found that invariant natural killer T (iNKT) cells could be directly activated by bacterial SAgs in a CD1d-independent manner (Hayworth et al, 2012), and Peter Szabo demonstrated a pathogenic role for iNKT cells in our in vivo TSS model (Szabo et al, 2017b). More recently, in a project spearheaded by Joshua Choi, a former doctoral student (currently a postdoctoral scholar at Harvard), we designed and successfully implemented a two-step experimental immunotherapeutic regimen in which T helper 2 (TH2)- and TH1-polarizing glycolipid agonists of iNKT cells were administered to relieve hyperinflammation and immunosuppression, respectively, in a mouse model of biphasic sepsis (Choi et al, 2021).
iNKT cells are relatively rare in humans. In contrast, another subset of unconventional innate-like T lymphocytes, called mucosa-associated invariant T (MAIT) cells, are abundant in the human peripheral blood and mucosal layers. Ryan Shaler, a former postdoctoral scholar (now an Associate Director at Sonata Therapeutics, Cambridge, MA), identified MAIT cells as the most prolific source of a select array of proinflammatory cytokines, including IFN-γ (but not IL-17A), in response to bacterial SAgs (Shaler et al, 2017). This overzealous response was dependent upon the engagement of MHC class II molecules, but not MHC-related protein 1 (MR1), and was largely mediated by IL-12 and IL-18 receptor signaling.
Furthermore, Ryan demonstrated that SAg-provoked MAIT cell responses were accompanied or followed by a cellular exhaustion program, which was mediated by lymphocyte-activation gene 3 (LAG-3), a targetable immune checkpoint, and which interfered with the cognate antimicrobial activities of MAIT cells. Therefore, a novel mechanism underlying SAg-elicited immunosuppression could be envisaged and proposed.
We consulted with Howard in most of the above studies, and he was more than willing to avail his expertise and to read and critique our articles. He congratulated us on the completion of our work on MAIT cell roles in toxic shock, which he graciously called “a real tour de force”. However, he often felt that his contributions did not warrant coauthorship. I felt differently but honored Howard's decision not to be listed as a formal author.
My trainees and I have benefited from Howard's ideas in various projects focused on cytokine storms elicited not only by SAgs and polymicrobial sepsis but also by respiratory infections with influenza A viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Some of these investigations will be wrapped up soon.
Howard continues to be a constant and consistent source of inspiration to my team and a role model in how best to pass the torch to the next generation of immunologists. On one occasion, after Peter Szabo and I found Howard during the 2017 annual American Association of Immunologists meeting in Washington D.C. (Fig. 1), he almost immediately introduced us to another giant of the field, Joost Oppenheim (1934–2022) (Wahl and Young, 2022), and proclaimed “these guys are trying to cure sepsis.” This powerful statement summarized our research dream and created an unmistakable and priceless sparkle of excitement in Peter's eyes.
Reconnecting with Dr. Howard Young during the 2017 American Association of Immunologists meeting in Washington D.C. Left to right: Peter Szabo, Howard Young, and Mansour Haeryfar.
Beyond our scientific endeavors, Howard has always been willing to lend his support to me with absolutely no strings attached. In fact, I do not recall receiving a negative or late reply from him to my numerous requests. One such request was time-sensitive and had to be made on Yom Kippur, but Howard responded within the needed time frame. Howard's unwavering friendship has been extraordinary especially in light of the fact that I did not formally train with him. I was simply fortunate that our paths crossed in our mutual pursuit of knowledge.
One needs to seek out guidance from trusted mentors throughout his/her entire life and career, and what better way to do it than to “stand on the shoulders of giants” like Dr. Howard Young to try to see as far as humanly possible! As we celebrate and highlight Howard's many scientific and mentoring achievements in this Festschrift, I feel honored to have known such an amazing scientist, mentor, and citizen and to have been given the opportunity to say a few words about him. I look forward to more fruitful interactions and collaborations with Howard for many years to come.
Footnotes
Author Disclosure Statement
No competing financial interests exist.
Funding Information
Invariant T cell studies in my laboratory are funded by the Canadian Institutes of Health Research (Project Grants 156295 and 174984), the Natural Sciences and Engineering Research Council of Canada (Discovery Grant 04706-2019 RGPIN), and the Canadian Cancer Society (Innovation Grant 706396).