New Findings Reshape Our Understanding of Human T Cell Biology

A study led by UC Irvine researchers reveals that T cells in human tissue differ from those found in blood, a finding that could lead to more accurate biomarkers of vaccine efficacy and immunotherapy outcomes.

Irvine, Calif., Dec. 1, 2025 — T cells are a central part of our body’s immune response to infection, playing a critical role in fighting pathogens and cancer, among many other diseases. Most clinical studies of human T cells rely on blood tests to track vaccine responses, immunotherapy effectiveness and chronic infections.

“Yet blood contains less than 2% of the body’s total T cells,” says Lisa Wagar, PhD, an assistant professor of physiology and biophysics in the UC Irvine School of Medicine. “The remaining 98% reside within tissues such as the lymph nodes, tonsils, spleen and mucosal sites.”

What happens when you compare peripheral blood T cells to the T cells that live in tissue?

“We performed deep sequencing of 5.7 million T cells from 10 donors, representing sampling depth unparalleled in previous studies” says Suhas Sureshchandra, a postdoctoral fellow in the Wagar Lab who led the team of multidisciplinary, multi-institutional researchers. “In our study, the central question addressed was how representative blood truly is of the body’s overall T cell activity and diversity.”

The findings, published in Immunity, reveal that T cells in human tissue are very different from T cells found in blood in terms of what they can respond to and how.

“By studying only blood samples, we have been underestimating the diversity of T cells in our body,” explains Sureshchandra. “Different flavors of T cells live in different locations, and only a fraction of those can be captured in blood.”

This key finding fundamentally reshapes our interpretation of human T cell biology.

“Tissue-specific immune responses that drive antibody production and local protection can be robust and functioning while remaining completely invisible in blood samples,” says Wagar. “This suggests that an absence of a detectable T cell response in blood doesn’t mean there’s no immune response occurring — it’s just that we’re looking in the wrong place!”

By quantifying what’s different between T cells in blood and tissue, the researchers hope to provide a framework for developing more accurate biomarkers of vaccine efficacy, protective responses against infections and immunotherapy outcomes.

They plan to extend this work beyond the tonsil to other human tissues, such as the spleen, lymph nodes and mucosal sites. Other studies include defining how tissue-specific repertoires and phenotypes change with age, infection and vaccination.

“Though blood sampling can be informative when timed correctly, in practice, the optimal timing is difficult to achieve,” says Wagar. “Therefore, we need to move away from ‘one-size-fits-all’ blood testing toward precision diagnostics that account for both circulating responses as well as tissue-specific immune responses.” This includes serial sampling of blood, along with tissue proxies such as nasal swabs (for respiratory), saliva (for oral), stool (for gastrointestinal), lymph node aspirates (for germinal center), and skin biopsies.

“Adding in tissue-specific samples and proxies,” stresses Wagar, “will provide a more comprehensive picture of T cell responses to interventions.”

This work was funded in part by the Wellcome Leap HOPE (Human Organs, Physiology, and Engineering) program and a National Institutes of Health (NIH) grant.

About the UC Irvine School of Medicine: Each year, the UC Irvine School of Medicine educates more than 500 medical students and over 180 PhD and MS students. Nearly 900 residents and fellows are trained at the UCI Medical Center and affiliated institutions. The School of Medicine offers multiple MD, PhD and MS degrees, and students are encouraged to pursue an expansive range of interests and options. The UC Irvine School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit medschool.uci.edu.

About the University of California, Irvine: Founded in 1965, UC Irvine is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UC Irvine has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UC Irvine, visit www.uci.edu.