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

Abstract

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؉ IntroductionThe term "naive T cell" derives from the assumption that CD4 ϩ T cells are antigen-inexperienced directly after their egress from the thymus until they are primed by foreign antigen and differentiate into memory/effector CD4 ϩ T cells. For the latter, a plethora of surface markers are used to define subpopulations, which differ with respect to stage of differentiation and effector functions, such as cytokine expression. This has proven to be beneficial for the analysis of CD4 ϩ T-cell function in physiologic circumstances as well as under pathologic conditions and helped to shape our current understanding of CD4 ϩ T-cell immunology. In contrast, naive, antigen-inexperienced CD4 ϩ T cells have so far mostly been regarded as an entity of uniformly behaving lookalikes differing only in T-cell receptor (TCR) specificities. With respect to a characteristic phenotype, human naive CD4 ϩ T cells have been considered to express CD45RA, CD62L, CD27, CD28, and CCR7 but to lack or to be characterized by low expression of molecules, such as CD45RO, CD11a, CD44, CD95, CXCR3, and CCR4. 1,2 In addition, naive CD4 ϩ T cells display characteristic functional capabilities, such as the ability to express interleukin-2 (IL-2). In contrast, they lack expression of classic effector cytokines, such as interferon-␥ and IL-4, a hallmark of antigen-experienced memory/ effector T cells. Reportedly, they also display unique calcium mobilization patterns and proliferative responses on stimulation. 3,4 Because they, by definition, have not undergone clonal selection during activation with a foreign antigen, they display a highly diverse TCR repertoire. 5 During recent years, a substantial number of studies have highlighted the importance of continuous contact with major histocompatibility complex (MHC) class II peptides for naive CD4 ϩ T cells, contrasting the definition of naive CD4 ϩ T cells as antigen-inexperienced. It was demonstrated that activation threshold, survival, and homeostatic prolifer...

In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency

“…10,[42][43][44] Our observation also supports the need for combining different markers (ie, TREC content and Ki67 expression) for a correct thymic output evaluation in human beings, as recently suggested by different authors. 45,46 In summary, our data show that T-cell reconstitution after GT for ADA-SCID, like allogeneic BMT, is driven by de novo thymopoiesis, as well as by homeostatic expansion of naive and memory T cells, especially in the first months after treatment.…”

Immunological memories of the bone marrow

“…It includes CD45RA memory stem cells75, 76 and CD45RA “terminally differentiated” effector memory T cells 77, 78. This zoo may even expand further in the future, considering that among naive T lymphocytes, those expressing CD31 are truly naive, ie, recent thymic emigrants, while those not expressing CD31 have lost their T‐cell receptor recombination excision circles 79, 80. This indicates that they had been activated to proliferate in the periphery.…”

Reduced naïve CD 8 + T ‐cell priming efficacy in elderly adults

“…However, the thymus atrophies with age, a process termed ‘thymic involution’ (Gruver et al ., 2007). This progressive decay in thymic function leads to a corresponding loss of naïve T‐cells and increased homeostatic proliferation within the naive T‐cell compartment (Kohler & Thiel, 2009; Sauce et al ., 2012). Nonetheless, such enhanced proliferation is insufficient to maintain the number (Sauce et al ., 2012) and clonotypic diversity (Naylor et al ., 2005) of peripheral naïve T‐cells in elderly adults.…”