This study uses a new technique to tell us that the cells in the blood are different to those in the immune organs…it is a bit of a NSS moment for me as we have known this for decades. Cells such as T cells are formed in the bone marrow and then educated in the the thymus (an organ above the heart) and then activated in lymph glands and have their effects in tissues. They use the blood to get from one organ to another. During this process the cells expand (in lymph glands) and differentiate and change their coats so they circulate through tissues. The naive T cells have different markers so they circulate round lymph glands, this way naive cells get activated by the pathogens as they get broken down and taken to the lymph glands by antigen presenting cells and the memory effector cells get into tissues to kill the pathogen. In the lymph glands of which the tonsil is one and the appendix is another and they get enlarged when there is infection and expansion of cells this is one of the reasons they get removed because of the painful enlargement from infection. Here they used a new technology to look at the cells and rather than stain them they looked at the genes they produce. Some of the cells from the lymph glands are not the major circulating cells and are different.
•5.7 million blood and tonsil T cells were profiled using single-cell RNA-seq
•Circulating T cells exhibit limited clonal overlap with their tonsillar counterparts
•Clonal prevalence and dominance of antigen-specific CD8 T cells varied by compartment
•Viral exposure is more influential on tonsillar repertoire diversity than blood
Sureshchandra S, Henderson J, Levendosky E, Bhattacharyya S, Kastenschmidt JM, Sorn AM, Mitul MT, Yates TB, Cheng E, Benchorin A, Batucal K, Daugherty A, Murphy SJH, Thakur C, Trask D, Ahuja G, Zhong Q, Moisan A, Tiffeau-Mayer A, Saligrama N, Wagar LE. Deep profiling of human T cells defines compartmentalized clones and phenotypic trajectories across blood and tonsils. Immunity. 2025 Dec 9;58(12):3130-3143.e8.
98% of T cells reside in tissues, yet nearly all human T cell analyses are performed on peripheral blood. We performed single-cell sequencing of 5.7 million T cells from autologous blood and tonsils of ten donors. We identified distinct patterns of clonal expansion associated with tonsil-restricted phenotypes. Clonal sharing between blood and tonsils was lower than previous estimates and increased with age. Identical T cell receptor (TCR) sequences exhibited limited concordance in their phenotypes across compartments. Furthermore, location dictated the frequencies, clonal dominance, and phenotypes of antigen-specific T cells. Using immune organoids, we showed that antigen exposure drives functionally distinct T cell clones from naive or tissue-resident memory pools. Finally, we demonstrate that chronic infections influence TCR repertoire diversity differently in blood and tonsil-resident T cells. These data highlight the necessity of accounting for tissue-specific contexts to accurately measure the TCR repertoire and monitor T cell responses following perturbing therapies.
Source: multiple-sclerosis-research.org