Tonsils and T cell development process

I have found yet another interesting publication that covers the thymocyte stage of T cell life. The understanding of this paper may require some extra effort to become acquainted with a number of cellular populations that are encountered along the stepwise T cell development process (unless you’re an expert on thymocyte maturation). But the conclusions are quite intriguing because according to authors the thymus may not be the only anatomical place which supports the organized production of mature T cells. This research is performed on human tonsilar samples that have been collected during routine tonsillectomies. Most presented data comprise the meticulous use of flow cytometry which is supported by real-time PCR and immunohistochemical staining.

The link: http://www.jci.org/articles/view/46125

Authors track the presence of putative T cell progenitors in human tonsils using markers associated with thymocyte development. These markers include CD34 (which is expressed on bone marrow-derived stem cells and lost along T cell differentiation), CD38 (whose increased expression denotes commitment to the T cell lineage) and CD1a (another surface protein associated with the stem cell to thymocyte transition). Initially investigators try to make sure if tonsils may be seeded by stem cells that are converting to thymocytes. It turns out that tonsilar CD34-positive and lineage negative population contains two subpopulations – CD38dim and CD38brigth. Another experiment identifies CD34+CD1a+ population which is divided into two distinct subsets: CD11c+CD10 cells (that are dendritic cells) and CD11cCD10+ cells (that may be putative thymocytes). Collectively, the first part of paper provides the evidence that human tonsils hold lineage negative populations whose surface marker expression is remarkably similar to developing thymocytes: CD34+CD38dim, CD34+CD38bright and CD34+CD1a+CD11c.

Another characteristic feature of thymocyte is the double positive stage when developing T lymphocytes express both CD4 and CD8 co-receptors and loose stem cell marker CD34. At this stage some thymocytes start also expressing the additional component of TCR complex – CD3. Authors compare CD34-negative DP cells from thymus, tonsils and blood to find that thymic DP population is exclusively CD1a-positive. Blood has only CD1a-negative DP cells (they are probably memory cells as joint CD4/CD8 expression is not exclusive for thymocytes) and tonsils hold a mixture of both. Remarkably, the tonsilar CD1a-positive DP population is identical to thymic DP cells as it is comprised of two subsets that are CD3 and CD3+. It is therefore concluded that human tonsils contain two additional thymocyte-like populations: CD34CD1a+CD4+CD8+CD3 and CD34CD1a+CD4+CD8+CD3+.

Authors follow up with thorough comparison of thymocyte-like populations from tonsils to corresponding cells collected from thymus by flow cytometry and observe general (but not absolute) similarities in surface marker expression in all studied subsets. It is also detected that tonsilar putative thymocytes match their thymus counterparts in gene expression patterns. Apart from that investigators employ immunohistochemistry staining to show that thymocyte-like cells localize to the discreet anatomical region of tonsil – fibrous scaffold. Finally, in a series of ex vivo experiments they demonstrate that tonsilar thymocytes have T cell differentiation potential (CD34+ thymocytes are apparently able to give rise not only to T cells but also to NK population).

The description of what looks like the complete T cell differentiation pathway outside the thymus is very intriguing. Authors collected their samples from children that have undergone tonsillectomy which means that they must have suffered numerous onsets of tonsil inflammation. May repetitive inflammatory events contribute to that unusual extrathymic production of T cells? And what can you think about their functional characteristics? Are tonsil-derived T cells subject to the central tolerance process?

McClory S, Hughes T, Freud AG, Briercheck EL, Martin C, Trimboli AJ, Yu J, Zhang X, Leone G, Nuovo G, & Caligiuri MA (2012). Evidence for a stepwise program of extrathymic T cell development within the human tonsil. The Journal of clinical investigation, 122 (4), 1403-15 PMID: 22378041

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