Tonsils turn out T cells too

Credit: S. Bradbrook

The thymus has long been known to be the site of T cell development and is required for the generation of a healthy T cell repertoire. Now, McClory et al. describe a stepwise programme of T cell development in human tonsils.

The authors carried out extensive flow cytometry analyses of cells isolated from human paediatric tonsils and compared them with known subsets of developing thymocytes. Five T cell populations, which were similar to various thymic developmental intermediates, were identified in the tonsils. Population one consisted of CD34⁺CD38^low cells that lacked expression of a range of lineage (LIN) markers, and population two were CD34⁺CD38^hiLIN⁻ cells. Low expression of CD38 by CD34⁺ cells identifies multipotent haematopoietic progenitors, and upregulation of CD38 expression is associated with their maturation. This suggests that these two populations represent the earliest stages of T cell development. Indeed, these cells resembled, but were not identical to, early double-negative thymocytes.

Upregulation of CD1a expression by CD34⁺ cells is associated with commitment to the T cell or dendritic cell (CD11c⁺) lineages. The third population identified in tonsils consisted of CD34⁺CD1a⁺CD11c⁻ cells. This population was remarkably similar to thymic CD34⁺CD1a⁺ double-negative thymocytes and expressed several other early T cell markers, including the lymphocyte-specific DNA polymerase terminal deoxynucleotidyl transferase (TdT; also known as DNTT).

CD34⁻CD1a⁺CD11c⁻CD3⁻ cells made up population four, and these cells also expressed CD4 and CD8, similarly to double-positive thymocytes. Population five expressed CD3 (CD34⁻CD1a⁺CD11c⁻CD3⁺ cells) and resembled CD3⁺ near-mature T cells in the thymus.

Furthermore, the expression pattern of various genes that are used to track thymocyte development (such as RAG1, PTCRA, BCL2L1 and ZBTB7B (encoding THPOK)) was similar in the corresponding tonsil populations. And, importantly, the authors showed that all five tonsil populations were capable of differentiating into T cells ex vivo.

Finally, TdT⁺ cells expressing CD34 and/or CD1a were shown to reside in regions near the fibrous scaffold of the tonsil. Furthermore, these regions expressed the Notch ligands Delta-like ligand 1 (DLL1) and DLL4, which are essential for T cell development. This suggests that these regions have a unique anatomical function that supports extrathymic T cell development.

So, these five subsets identified in human tonsils would appear to represent intermediates in a programme of extrathymic T cell development. Although, the contribution of this extrathymic T cell development pathway to the healthy T cell repertoire remains to be determined, it may augment the T cell pool in settings of poor thymic function.