T Cells in Tonsils Are Surprisingly Different From Those in Blood and That Could Change How We Study Immunity

T cells, also called lymphocytes, are one of the most important components of the human immune system. They help the body recognize infections, respond to vaccines, and play a central role in modern immunotherapies used to treat cancer and autoimmune diseases. For decades, scientists have relied almost entirely on blood samples to study how T cells behave. Blood is easy to collect, widely available, and convenient for repeated testing.

However, new research shows that this long-standing approach may be giving us only a partial picture of how human immunity truly works.

A major study published in the journal Immunity reveals that T cells found in tonsils differ in critical ways from those found in the bloodstream, even when they come from the same individual. These differences are not subtle. They affect how T cells develop, what antigens they recognize, and how they function in immune responses. The findings suggest that blood-based immune monitoring may miss key information, especially when evaluating vaccines and immunotherapies.

A Massive Study of Human T Cells

The research was led by Naresha Saligrama, an assistant professor of neurology and of pathology and immunology at Washington University School of Medicine in St. Louis, in collaboration with scientists from the University of California, Irvine, and several other institutions.

To carry out the study, the researchers analyzed 5.7 million individual T cells, making this one of the largest single-cell datasets of human T cells ever assembled. These cells were collected from both tonsil tissue and blood from 10 healthy donors undergoing tonsillectomy. The donors ranged in age from infants to adults, allowing the team to examine how immune differences appear across the human lifespan.

Using advanced single-cell sequencing techniques, the researchers were able to examine not only the genetic identity of each T cell but also its functional state, developmental pathway, and antigen recognition potential.

Blood T Cells Represent Only a Small Fraction of Immunity

One of the most striking facts highlighted by the study is that less than 2% of the body’s total T cells are found in the blood. The vast majority reside in tissues, including the lymphatic system (such as lymph nodes, spleen, and tonsils) and non-lymphatic tissues like the gut, skin, and lungs.

Despite this, blood has remained the gold standard for immune monitoring. Researchers routinely use blood samples to measure how T cells respond to infections, vaccines, and immune-based treatments. This new work strongly suggests that such measurements may not fully reflect what is happening in the body’s tissues, where immune responses actually take place.

Clear Differences Between Tonsil and Blood T Cells

When the researchers compared T cells from tonsils and blood drawn from the same individuals, they found significant differences in nearly every aspect they examined.

T cells in the tonsils showed distinct phenotypes, meaning they expressed different sets of genes and surface markers compared to blood T cells. Even when T cells shared the same T cell receptor (TCR) — indicating they came from the same clonal origin — their behavior and functional characteristics varied depending on whether they were located in blood or tonsil tissue.

This demonstrates that location matters. The tissue environment itself plays a major role in shaping how T cells function, independent of their genetic identity.

Specialized T Cells Prefer Tissues, Not Blood

The study also confirmed that several important T cell subtypes are largely absent from the bloodstream. Two key examples are:

• Resident memory T cells, which remain embedded in tissues and provide rapid local protection against previously encountered pathogens
• T follicular helper cells, which are essential for helping B cells produce high-quality antibodies

These specialized cells were found primarily in tonsil tissue and were rarely detected in blood samples. This finding is especially important because both cell types play major roles in vaccine responses and long-term immune protection.

Clonal Sharing Is Lower Than Expected

Another major discovery involved clonal sharing, which refers to identical T cell clones appearing in both blood and tissue. The researchers found that clonal overlap between blood and tonsil T cells was much lower than previously assumed.

Interestingly, clonal sharing increased with age, suggesting that immune cell circulation between tissues and blood may change over time. Still, even in adults, the overlap remained limited, reinforcing the idea that blood does not fully represent tissue immunity.

Why Tonsils Are a Valuable Window Into Immunity

Tonsils are part of the body’s secondary lymphoid organs and play a critical role in immune surveillance, especially for pathogens entering through the mouth and nose. Because tonsils are relatively accessible during routine surgeries, they provide a rare opportunity to study human tissue-resident immune cells directly.

The authors emphasize that tonsils may serve as a powerful model system for understanding how immune responses are organized in tissues, something that cannot be easily captured through blood samples alone.

Implications for Vaccines and Immunotherapy

These findings have important consequences for how scientists and clinicians evaluate immune responses. If blood samples fail to capture key T cell populations and behaviors, then assessments of vaccine effectiveness, immune memory, and immunotherapy outcomes may be incomplete or misleading.

The study suggests a growing need to either incorporate tissue-based immune monitoring or develop better surrogate markers that reflect tissue immunity more accurately. This could lead to more precise diagnostics and more effective immune-based treatments.

The Bigger Picture of Tissue-Specific Immunity

This research fits into a broader shift in immunology toward understanding tissue-specific immune responses. Immune cells adapt to their local environments, and these adaptations influence how they fight infections, control inflammation, and respond to therapies.

The authors note that tonsils are only one tissue type. To fully understand human immunity, future studies will need to examine T cells in other locations such as the lungs, gut, skin, and lymph nodes.

Looking Ahead

The study was supported by significant research funding, including backing from initiatives focused on using human tonsil cultures to explore immune mechanisms in more realistic biological settings. The researchers hope their work will encourage the scientific community to move beyond blood-only approaches and embrace a more comprehensive view of immune function.

In short, this research makes one thing clear: where a T cell lives matters just as much as what it is. Understanding that distinction could reshape how we study immunity for years to come.

Research paper:
https://doi.org/10.1016/j.immuni.2025.10.025