Thymic emigrants: TRECs and CD31+CD4+ T cells
YOUNG RESEARCHERS' CORNER Spring 2011, by Sara Ciullini Mannurita
I would like to invite all ESID junior researchers and clinicians to make their contribution to the Young Researcher Corner taking part actively writing for the newsletter.
This is my turn again and this time the topic is “Thymic emigrants: TRECs and CD31+CD4+ T cells”
T cell reconstitution is a critical feature of the recovery of the adaptive immune response and has two main components: thymic output of new T cells and peripheral homeostatic expansion of pre-existing T cells. It has been shown that though thymic function declines with age, substantial output is still maintained into late adult life. In many clinical situations, thymic output is crucial to the maintenance and competence of the T cell effector immune response.
Thymic function can be determined by evaluation of recent thymic emigrants (RTE). They are naïve peripheral T cells, which have only recently exited the thymus and have not undergone further peripheral proliferation and antigen selection. Classically they that are assessed by the direct analysis of TRECs (T cell receptor excision cyrcles) within mononuclear or CD4+ T cells. TRECs are episomal DNA excision products of the T cell receptor gene rearrangements that occur in maturing thymocytes. They are stable, then do not degrade over time and they do not divide when a cell divides, resulting to be diluted during cell divisions. TRECs are expressed only in T cells of thymic origin and each cell contains a single copy of TREC. Therefore, TREC analysis provides a very specific assessment of T cell recovery or T cell competence. Detection of TRECs following transplantation of thymic o stem cells does indicate functional T cell maturation, which indeed is correlated with restoration of naïve T cell numbers, broadening of the TCR repertoire and restoration of T cell function.
In vivo TCR gene excision leads to several TRECs and the TCR delta deletion TREC (REC-J signal joint TREC or sj-TREC), that is produced late in maturation by 70% of developing human T cells that express TCRs, has been shown to be the most accurate TREC for measuring thymic output. TRECs can be quantified using several PCR-based methods and the real-time quantitative PCR is preferred because of its sensitivity accuracy and because it is based on specific detection of the amplified target sequence during each PCR cycle.
Recently the surface molecule CD31 (PECAM-1) has been proposed as a marker expressed preferentially by naïve TREC-rich cells that have undergone a low number of cell divisions. CD31 is a member of the Ig superfamily expressed on a variety of cell types including T cells, NK cells, monocytes, granulocytes, platelets and mast cells. It has been demonstrated that CD31 can be used to distinguish CD31+ thymic naïve and CD31- central naïve CD4+ T cells in peripheral blood. The majority of CD31+CD4+ T cells are CD31+ naïve CD45RA+CD4+ T that have a high TREC content and they show an age-dependent decrease in absolute count and frequencies among naïve CD4+ T cells. In addition the decrease of absolute number of CD31+ naïve CD4+ T cell in peripheral blood correlate with the decline of TRECs amount. In contrast central naïve T cells don’t express CD31 and show a low amount of TRECs, implying they have extensively proliferated. Moreover CD31+ naïve CD4+ T cells show high telomerase activity and preserve telomere, which is typical of CD4+ T cells at the early stages of development and of low replicative history.
Studies reported in lymphopenic children after hematopoietic stem cells transplantation demonstrated the expression of CD31 in reemerging CD45RA+CD4+ T cell in the 12 months after the transplantation, besides at 5-month after transplantation reemerging CD31+CD4+ and CD45RA+CD4+ T cells correlate with reappearing absolute number of TRECs.
CD31+ thymic naïve CD4+ T cells can be easily evaluate by cytofluorimetric analysis using minute amount of blood.
Thus, similarly to TRECs quantification, CD31 expression on CD4+ T cells seems to be a suitable marker for thymic function evaluation, reactivation after HSCT and evaluation of immune competence.
Is important to consider that interpretation of TRECs analysis is hampered by the fact that homeostatic proliferation resulting in change of composition of the analyzed T cell population influences the results. In this condition it will be useful the evaluation of both CD31+ thymic naïve and CD31- central naïve CD4+ T cell because proliferation would be associated with an increase of CD31- central naïve CD4+ T cells.
By: Sara Ciullini Mannurita
Chan K, Puck JM. Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol. 2005 Feb;115(2):391-8.
Hazenberg MD, Verschuren MCM, Hamann D, et al. T cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation. J Mol Med 2001;79:631-640
Junge S, Kloeckener-Gruissem B, Zufferey R et al. Correlation between recent thymic emigrants and CD31+ (PECAM-1) CD4+ T cells in normal individuals during aging and in lymphopenic children. Eur J Immunol. 2007 Nov;37(11):3270-80.
Kimming S, Przybylski GK, Schmidt CA. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood.
J Exp Med. 2002 Mar 18;195(6):789-94.
Kohler S, Thiel A. Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets. Blood. 2009 Jan 22;113(4):769-74. Epub 2008 Jun 26.
ESID would like to thank Sara for her continous work and efforts to provide excellent articles and keep our website and newsletter interesting and updated!