Biography

Dr. McKinstry completed his PhD at the University of Saskatchewan (Canada) followed by postdoctoral training at the Trudeau Institute in Saranac Lake, New York.  He was an Assistant Professor in the Department of Pathology at the University of Massachusetts Medical School prior to his recruitment to the University of Central Florida in 2015.  Dr. McKinstry’s research is focused on T cell immunobiology.  The long-term goal of his research is to improve vaccine-induced protection against pandemic threats like influenza A virus (IAV).

Current vaccines against all pathogens aim primarily to generate high titers of neutralizing antibodies that will recognize and bind to the specific pathogen, thereby preventing infection. IAV vaccines target antibody production against the viral hemagglutinin (HA) and neuraminidase (NA) proteins that are key for facilitating entry into host cells and the release of new viral particle from infected cells, respectively. However, IAV rapidly mutates to escape recognition by neutralizing antibodies, and this largely underlies the need for annual vaccine reformulation, based on predictions of which HA and NA molecules will be expressed by seasonal IAV variants. Current vaccines are thus of low protective efficacy in cases of mismatch between the HA and NA molecules present in the vaccine versus those expressed by circulating seasonal strains. Perhaps more importantly, this vaccination approach is also ineffective when unexpected pandemic IAV strains, such as the ‘bird flu’ or ‘swine flu’, emerge and circulate in the human population.

CD4 T cells, traditionally labeled as the ‘helper’ cells of the immune system, have been shown to exert several powerful anti-viral functions. Evidence from animal models of IAV infection and clinical studies suggest that memory CD4 T cells can provide strong protection against several pathogens, including IAV, even in the absence of neutralizing antibodies.  Furthermore, CD4 T cells can recognize viral antigens expressed by infected cells that are highly conserved between different seasonal and pandemic IAVs.  Thus, as opposed to standard antibody-based vaccination, T cell-based vaccines offer a platform for ‘universal’ protection irrespective of the specific IAVs that happen to be prevelant during a particular ‘flu’ season.  There is thus high enthusiasm for harnessing IAV-specific CD4 T cells as a protective component of next-generation IAV vaccines.

The McKinstry Lab is focused on two fundamental questions that need to be addressed in order to incorporate protective CD4 T cells into vaccine strategies. First, how do CD4 T cells combat IAV? While studies have identified that several different specialized subsets of memory CD4 T cells contribute to viral clearance, work from the lab has shown that major transcriptional pathways needed for generating protective CD4 T cell responses against other viruses and intracellular pathogens (driven by T-bet and Eomesodermin) are not required to prime CD4 T cells able to effectively clear IAV.  Current research in the lab thus seeks to identify how signals that are not traditionally associated with antiviral CD4 T cell responses can be harnessed to promote potent anti-viral responses.  While most analysis along these lines focuses on functional attributes linked to the so-called ‘Th1’ subset of CD4 T cells, recent findings indicate that ‘Th17’ functions too can be highly protective, and that functions shared between Th1 and Th17 cells, that are often overlooked, may represent a particularly important target for vaccination in the case of IAV.

The lab’s second focus is understanding how the most protective memory CD4 T cells can be generated through vaccination. Current vaccines do not stimulate the formation of strong T cell immunity, and indeed, signals important in directing memory T cell survival remain poorly understood.  Recent studies have shown that memory T cells able to survive long-term at sites of infection (or vaccination) are crucial for providing optimal protection upon rechallenge. The signals needed to form such ‘tissue-resident’ memory T cells are not clear but seem to be distinct from the signals that drive the generation of memory cells present in secondary lymphoid organs.  Data from the lab also indicates that the timing of when pro-memory signals are received by CD4 T cells responding to IAV is a critical variable determining their efficacy.  Thus, defining critical elements of the pathway supporting tissue-resident memory CD4 T cell generation in the lung (the site of IAV infection), and when they act, will allow for innovative vaccine strategies to improve protection against IAV and other important respiratory pathogens by better targeting durable cellular immunity.

The McKinstry lab is funded by NIH and the American Heart Association, and has collaborated with a number of other labs at UCF.  For a complete list of publications (PubMed) and citation information (Google Scholar), please click on the links below:

https://www.ncbi.nlm.nih.gov/myncbi/karl.mckinstry.1/bibliography/public/

https://scholar.google.com/citations?user=IqPjp0QAAAAJ&hl=en