Homeostatic control of T-cell generation in neonates

Abstract

IntroductionDe novo T-cell generation requires a functional thymus. 1 The current paradigm is that the human T-cell repertoire is established during late fetal development and that, by the time of birth, thymectomy does not cause immediate immunodeficiency. 2,3 Thymic epithelial space-the component of the thymus relevant for T-cell production and selectioninvolutes rapidly after birth. Thymic involution starts at the age of 1 year and continues with a yearly loss of 3%. 4,5 The peripheral T-cell compartment is under homeostatic control 6 ; with the reduction in thymopoietic capacity, alternative mechanisms of T-cell generation are necessary to prevent lymphopenia. Autoproliferation of postthymic T cells, particularly those in the memory compartment, is now accepted as a mechanism of T-cell production. 7,8 With advancing age, a shift occurs from efficient thymic lymphopoiesis to T-cell generation through peripheral replication; however, both mechanisms likely coexist during adult life. Age-related loss of thymic function is not the only condition that necessitates alternative means of repopulating the T-cell compartment. A number of clinical conditions, including chemotherapy, bone marrow transplantation, and infection with human immunodeficiency virus, are associated with T-cell depletion and the subsequent need to regenerate T cells despite limited thymopoietic capability. Evidence shows that recovery of peripheral T-cell numbers after chemotherapy is from thymic sources in children younger than 18 years of age. 7 In adults, thymopoiesis may still contribute to some degree, but replication of peripheral T cells becomes the dominant mechanism of filling the pool. It is obvious that the proliferation of postthymic T cells, especially when not entirely random, can have profound consequences on the composition of the T-cell repertoire. 9,10 What precisely these consequences are for immunocompetence is not understood.Functionality of the immune system is tightly linked to the receptor diversity of the T-cell pool. 11,12 Obviously, a large spectrum of T-cell receptors (TCRs) increases the chances of recognizing invading microorganisms. Thymopoiesis, the single mechanism of creating novel T cells, should be the key factor in determining immunocompetence. Young adults carry approximately 2 ϫ 10 11 CD4 ϩ T cells and approximately 1 ϫ 10 11 CD8 ϩ T cells. 13,14 The highest degree of diversity would be obtained if each naive T cell in the pool had a unique TCR. However, such a high degree of diversity might not be advantageous because it would decrease the probability of antigen recognition at a given tissue site. Instead, a minimal clonal size for each naive T-cell specificity is required to increase the chance for a T cell to encounter antigen and to mount a defensive response. Generation of a minimal clonal size requires that T cells selected in the thymus undergo intrathymic or postthymic proliferation.Arstila et al 15 have estimated the clonal size of naive T cells in adult humans. They measured an average diversity ...

Peripheral selection rather than thymic involution explains sudden contraction in naive CD4 T-cell diversity with age

“…We begin the simulations with young adults (20 y) at which time the rate of emigration of new TCR lineages from the thymus should roughly balance the rate of lineage loss due to stochastic extinction or conversion to memory. This approach allows us to circumvent complexities in the generation of the repertoire during development and in the very young when both thymic emigration and the total number of immune cells change dramatically (34,35). We assume that a combination of intra-and postthymic divisions lead to an initial clone size of s = 500 cells for a new thymic emigrant in an adult individual.…”

Protein tyrosine kinase 7: a novel surface marker for human recent thymic emigrants with potential clinical utility

“…28 This model is supported by the ability of exogenous IL-7 to expand the human naive CD4 T-cell compartment in vivo. 24 Interestingly, an increased fraction of naive CD4 T cells in the neonatal circulation are proliferating, 29,30 and this appears to be due to an increased sensitivity of neonatal naive CD4 T cells to IL-7, 31,32 a cytokine that is produced mainly by non-hematopoietic cells of the thymus, such as thymic epithelial cells, and the peripheral lymphoid organs. This increased sensitivity to IL-7 is also observed in human CD4 þ CD8À thymocytes, 33 suggesting that neonatal CD4 T cells retain a thymocyte-like response to this The dRec-cJd rearrangement also generates a sjTREC, which is commonly used for monitoring peripheral T-cell populations for their recent thymic origin using real-time quantitative PCR.…”

Aging and T-cell diversity☆

“…Estimates of clonal sizes have come from the dilution of TRECs during thymic development (Douek et al, 1998;Okamoto et al, 2002). We have used TREC measurements in cord blood of babies born at different gestational ages (Schonland et al, 2003). These different studies have allowed estimating the clonal size of naïve T cells to involve about 100 cells.…”