April 09, 2019

Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells

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RS13644 Casey Weaver 3 scrCasey Weaver, M.D., professor in the Department of Pathology, is the latest winner of the School of Medicine’s Featured Discovery. This initiative celebrates important research from School of Medicine faculty members. Dr. Weaver and colleagues discovered that differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells. This knowledge, published in Science, could be key to producing more effective vaccines, helping clinicians fight difficult pathogens, and understanding how to dampen autoimmune diseases. Read more from UAB News here.

The School of Medicine communications staff sat down with Dr. Weaver to gain insights about his research, UAB and the science community.

Q: What compelled you to pursue this research?

This study grew out of findings made with a good colleague with whom I began to collaborate immediately after joining the UAB faculty 25+ years ago—Dr. Pat Bucy. We found that only a fraction of “naive” or inexperienced CD4 T cells were able to produce the immune cytokine, IL-2, following activation. Activation of naive T cells leads to their differentiation into “mature” or effector T cells that have enhanced functional properties that allow them to regulate immune responses. The fact that there was unexpected hetereogeneity in the production of IL-2 by naive T cells—despite similar conditions of activation—raised the possibility that activated T cells that do, or do not, produce IL-2 might have different developmental fates and functions in immunity. Clearly, it took us a while to develop the appropriate tools to address this, but it proved to be worth the wait.

Q: What was your most unexpected finding?

The finding that the fraction of naive T cells that produce IL-2 are fated to become a type effector T cell called a follicular helper (or Tfh) cell, which assists other lymphocytes—B cells—to produce antibodies that combat infection, was a surprise. This was unexpected because it had been shown previously, in a nice study led by UAB investigators Dr. Andre Ballestros-Tato and Dr. Troy Randall, that IL-2 inhibits the differentiation of Tfh cells. Our results were therefore exactly opposite of what we had predicted. As it turns out, the IL-2 producers are resistant to IL-2 signaling themselves, but provide IL-2 in trans to non-IL-2 producers that use this signal to develop down a non-Tfh pathway.

Q: What is your research’s relevance to human disease?

It’s difficult to predict how our findings will impact the broader community, but our results now open a window to explore the early events in the “decision-making" of CD4 T cells to become either Tfh cells or non-Tfh effector cells.

Q: When did you know you had an important discovery?

When we found that depletion of the IL-2 positive T cells during an infection virtually eliminated Tfh cells while leaving non-Tfh effector cells intact, we knew we were on to something unexpected and potentially important.

Q: How has being at UAB and living in Birmingham affected your research?

I’ve been very fortunate to develop a career at UAB because my group has benefited from the tremendous support of the UAB leadership—both within and outside of my department. Any success I’ve had is really a credit to the research environment here: excellent resources, great colleagues, and outstanding trainees. Science is a team sport, and I draw a lot of energy and inspiration from those around me, particularly the trainees. The most rewarding aspect of this endeavor is seeing those around you succeed. UAB and Birmingham provide an environment that has allowed that to happen.

Read the publication here.