Tracking Naïve CD4 T Cells After They Leave The Thymus

A new paper in the Journal of Experimental Medicine reports that protein tyrosine kinase 7 (PTK7) is a surface marker that can be used to identify naïve CD4 T cells that have very recently exited the thymus (also called recent thymic emigrants or RTEs). Tracking thymic production of RTEs is important for monitoring immune reconstitution in many settings, including HIV infection, but reliable markers of this population have proven elusive. Christopher Haines and colleagues took the same type of approach that led to the identification of the molecule PD-1: they conducted gene expression studies of sorted CD4 T cell populations and found that PTK7 was significantly upregulated in thymocytes and neonatal CD4 T cells, but not adult CD4 T cells. Based on these findings, an antibody to PTK7 was used to quantify CD4 T cells expressing the protein on their surface. In an analysis of CD4 T cells sampled from 22 people across a wide range of ages (from 1 month to 61 years), PTK7-expressing naïve CD4 T cells were found to be abundant in neonates and levels subsequently declined progressively with aging.

The researchers also looked at the level of PTK7 expression on naïve T cells that either expressed or lacked the surface molecule CD31; loss of CD31 expression is associated with post-thymic proliferation of naïve CD4 T cells (see the free access review in the new issue of Blood, also appended below). Consistent with their other findings, PTK7 expression was restricted to CD31+ naïve CD4 T cells. Interestingly, the CD31+ naïve CD4 T cells could also be divided into two subsets based on whether they expressed PTK7, suggesting that CD31+ naïve T cells are not homogenous in terms of their proliferative history.

The study authors also report that PTK7+ naïve CD4 T cells are somewhat less efficient at mounting antigen-specific immune responses compared to PTK7- cells, due to delayed IL-2 production. They note that this may explain the poor Th1 CD4 T cell responses that have been described in neonates, because at this stage of development the vast majority of naïve CD4 T cells are RTEs expressing PTK7.

The Journal of Experimental Medicine

Published online January 26, 2009

doi:10.1084/jem.20080996

BRIEF DEFINITIVE REPORT

Human CD4+ T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function

Christopher J. Haines1, Thierry D. Giffon1, Li-Sheng Lu1, Xiaowei Lu2, Marc Tessier-Lavigne2, Douglas T. Ross3, and David B. Lewis1

1 Department of Pediatrics and the Immunology Program, 2 Department of Biological Sciences and Howard Hughes Medical Institute, and 3 Department of Biochemistry, Stanford University, Stanford, CA 94305

CD4+ recent thymic emigrants (RTEs) comprise a clinically and immunologically important T cell population that indicates thymic output and that is essential for maintaining a diverse β–T cell receptor (TCR) repertoire of the naive CD4+ T cell compartment. However, their frequency and function are poorly understood because no known surface markers distinguish them from older non-RTE naive CD4+ T cells. We demonstrate that protein tyrosine kinase 7 (PTK7) is a novel marker for human CD4+ RTEs. Consistent with their recent thymic origin, human PTK7+ RTEs contained higher levels of signal joint TCR gene excision circles and were more responsive to interleukin (IL)-7 compared with PTK7– naive CD4+ T cells, and rapidly decreased after complete thymectomy. Importantly, CD4+ RTEs proliferated less and produced less IL-2 and interferon- than PTK7– naive CD4+ T cells after β-TCR/CD3 and CD28 engagement. This immaturity in CD4+ RTE effector function may contribute to the reduced CD4+ T cell immunity observed in contexts in which CD4+ RTEs predominate, such as in the fetus and neonate or after immune reconstitution. The ability to identify viable CD4+ RTEs by PTK7 staining should be useful for monitoring thymic output in both healthy individuals and in patients with genetic or acquired CD4+ T cell immunodeficiencies.

Blood, 22 January 2009, Vol. 113, No. 4, pp. 769-774.

Prepublished online as a Blood First Edition Paper on June 26, 2008; DOI 10.1182/blood-2008-02-139154.

REVIEW ARTICLE

Life after the thymus: CD31+ and CD31– human naive CD4+ T-cell subsets

Siegfried Kohler1, and Andreas Thiel1,2

1 Clinical Immunology Group, Deutsches Rheuma-Forschungszentrum Berlin, Berlin; and 2 Regenerative Immunology and Aging, Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany

Early in life, thymic export establishes the size and the diversity of the human naive T-cell pool. Yet, on puberty thymic activity drastically decreases. Because the overall size of the naive T-cell pool decreases only marginally during ageing, peripheral postthymic expansion of naive T cells has been postulated to account partly for the maintenance of T-cell immunity in adults. So far, the analysis of these processes had been hampered by the inability to distinguish recent thymic emigrants from proliferated, peripheral, naive T cells. However, recently, CD31 has been introduced as a marker to distinguish 2 subsets of naive CD4⁺ T cells with distinct T-cell receptor excision circle (TREC) content in the peripheral blood of healthy humans. Here, we review studies that have characterized TREC^hi CD31^{+ thymic}naive CD4⁺ T cells and have accordingly used the assessment of this distinct subset of naive CD4⁺ T cells as a correlate of thymic activity. We will discuss further potential clinical applications and how more research on CD31^{+ thymic}naive and CD31^{– central}naive CD4⁺ T cells may foster our knowledge of the impact of thymic involution on immune competence.