Abstract
Thymocytes and thymic epithelial cells (TECs) cross-talk is essential to support T cell development and preserve thymic architecture and maturation of TECs and Foxp3+ natural regulatory T cells. Accordingly, disruption of thymic lymphostromal cross-talk may have major implications on the thymic mechanisms that govern T cell tolerance. Several genetic defects have been described in humans that affect early stages of T cell development [leading to severe combined immune deficiency (SCID)] or late stages in thymocyte maturation (resulting in combined immunodeficiency). Hypomorphic mutations in SCID-causing genes may allow for generation of a limited pool of T lymphocytes with a restricted repertoire. These conditions are often associated with infiltration of peripheral tissues by activated T cells and immune dysregulation, as best exemplified by Omenn syndrome (OS). In this review, we will discuss our recent findings on abnormalities of thymic microenvironment in OS with a special focus of defective maturation of TECs, altered distribution of thymic dendritic cells and impairment of deletional and non-deletional mechanisms of central tolerance. Here, taking advantage of mouse models of OS and atypical SCID, we will discuss how modifications in stromal compartment impact and shape lymphocyte differentiation, and vice versa how inefficient T cell signaling results in defective stromal maturation. These findings are instrumental to understand the extent to which novel therapeutic strategies should act on thymic stroma to achieve full immune reconstitution.
| Original language | English |
|---|---|
| Article number | 259 |
| Journal | Frontiers in Immunology |
| Volume | 5 |
| Issue number | JUN |
| DOIs | |
| Publication status | Published - 2014 |
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Keywords
- Central tolerance
- Omenn and leaky SCID models
- Rag deficiency
- Thymic cross-talk
- Thymic reconstitution
- Thymus
ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
Cite this
Rag defects and thymic stroma : Lessons from animal models. / Marrella, Veronica; Poliani, Pietro Luigi; Notarangelo, Luigi Daniele; Villa, Anna.
In: Frontiers in Immunology, Vol. 5, No. JUN, 259, 2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Rag defects and thymic stroma
T2 - Lessons from animal models
AU - Marrella, Veronica
AU - Poliani, Pietro Luigi
AU - Notarangelo, Luigi Daniele
AU - Villa, Anna
PY - 2014
Y1 - 2014
N2 - Thymocytes and thymic epithelial cells (TECs) cross-talk is essential to support T cell development and preserve thymic architecture and maturation of TECs and Foxp3+ natural regulatory T cells. Accordingly, disruption of thymic lymphostromal cross-talk may have major implications on the thymic mechanisms that govern T cell tolerance. Several genetic defects have been described in humans that affect early stages of T cell development [leading to severe combined immune deficiency (SCID)] or late stages in thymocyte maturation (resulting in combined immunodeficiency). Hypomorphic mutations in SCID-causing genes may allow for generation of a limited pool of T lymphocytes with a restricted repertoire. These conditions are often associated with infiltration of peripheral tissues by activated T cells and immune dysregulation, as best exemplified by Omenn syndrome (OS). In this review, we will discuss our recent findings on abnormalities of thymic microenvironment in OS with a special focus of defective maturation of TECs, altered distribution of thymic dendritic cells and impairment of deletional and non-deletional mechanisms of central tolerance. Here, taking advantage of mouse models of OS and atypical SCID, we will discuss how modifications in stromal compartment impact and shape lymphocyte differentiation, and vice versa how inefficient T cell signaling results in defective stromal maturation. These findings are instrumental to understand the extent to which novel therapeutic strategies should act on thymic stroma to achieve full immune reconstitution.
AB - Thymocytes and thymic epithelial cells (TECs) cross-talk is essential to support T cell development and preserve thymic architecture and maturation of TECs and Foxp3+ natural regulatory T cells. Accordingly, disruption of thymic lymphostromal cross-talk may have major implications on the thymic mechanisms that govern T cell tolerance. Several genetic defects have been described in humans that affect early stages of T cell development [leading to severe combined immune deficiency (SCID)] or late stages in thymocyte maturation (resulting in combined immunodeficiency). Hypomorphic mutations in SCID-causing genes may allow for generation of a limited pool of T lymphocytes with a restricted repertoire. These conditions are often associated with infiltration of peripheral tissues by activated T cells and immune dysregulation, as best exemplified by Omenn syndrome (OS). In this review, we will discuss our recent findings on abnormalities of thymic microenvironment in OS with a special focus of defective maturation of TECs, altered distribution of thymic dendritic cells and impairment of deletional and non-deletional mechanisms of central tolerance. Here, taking advantage of mouse models of OS and atypical SCID, we will discuss how modifications in stromal compartment impact and shape lymphocyte differentiation, and vice versa how inefficient T cell signaling results in defective stromal maturation. These findings are instrumental to understand the extent to which novel therapeutic strategies should act on thymic stroma to achieve full immune reconstitution.
KW - Central tolerance
KW - Omenn and leaky SCID models
KW - Rag deficiency
KW - Thymic cross-talk
KW - Thymic reconstitution
KW - Thymus
UR - http://www.scopus.com/inward/record.url?scp=84905655909&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84905655909&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2014.00259
DO - 10.3389/fimmu.2014.00259
M3 - Article
AN - SCOPUS:84905655909
VL - 5
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
IS - JUN
M1 - 259
ER -