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Modes of Antigen Presentation by Lymph Node Stromal Cells and Their Immunological Implications.

Hirosue S, Dubrot J - Front Immunol (2015)

Bottom Line: Transfer of antigen between LNSC and dendritic cells in both directions has been recently suggested to promote tolerogenic roles of LNSCs on the CD4(+) T cell compartment.Thus, antigen presentation by LNSCs is thought to be a mechanism that promotes the maintenance of peripheral tolerance as well as generates a pool of diverse antigen-experienced T cells for protective immunity.This review aims to integrate the current and emerging literature to highlight the importance of LNSCs in immune responses, and emphasize their role in antigen trafficking, retention, and presentation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioengineering, École Polytechnique Fédéral de Lausanne , Lausanne , Switzerland.

ABSTRACT
Antigen presentation is no longer the exclusive domain of cells of hematopoietic origin. Recent works have demonstrated that lymph node stromal cell (LNSC) populations, such as fibroblastic reticular cells, lymphatic and blood endothelial cells, not only provide a scaffold for lymphocyte interactions but also exhibit active immunomodulatory roles that are critical to mounting and resolving effective immune responses. Importantly, LNSCs possess the ability to present antigens and establish antigen-specific interactions with T cells. One example is the expression of peripheral tissue antigens, which are presented on major histocompatibility complex (MHC)-I molecules with tolerogenic consequences on T cells. Additionally, exogenous antigens, including self and tumor antigens, can be processed and presented on MHC-I complexes, which result in dysfunctional activation of antigen-specific CD8(+) T cells. While MHC-I is widely expressed on cells of both hematopoietic and non-hematopoietic origins, antigen presentation via MHC-II is more precisely regulated. Nevertheless, LNSCs are capable of endogenously expressing, or alternatively, acquiring MHC-II molecules. Transfer of antigen between LNSC and dendritic cells in both directions has been recently suggested to promote tolerogenic roles of LNSCs on the CD4(+) T cell compartment. Thus, antigen presentation by LNSCs is thought to be a mechanism that promotes the maintenance of peripheral tolerance as well as generates a pool of diverse antigen-experienced T cells for protective immunity. This review aims to integrate the current and emerging literature to highlight the importance of LNSCs in immune responses, and emphasize their role in antigen trafficking, retention, and presentation.

No MeSH data available.


Related in: MedlinePlus

Exogenous antigen distribution in the lymph node is choreographed by stromal cells. Lymph-borne peripheral exogenous antigens arrive in the lymph node (LN) via the afferent lymphatic vessels as fast-draining soluble or slow arriving cell-associated forms. Floor and ceiling lymphatic endothelial cells (LECs, violet) are the first stromal cells encountered by the antigens in the subcapsular sinus (SCS). Soluble antigens can be taken up and sequestered by LECs(a), while the remaining fraction of antigens leave the SCS: lower molecular weight antigens are channeled to conduits surrounded by fibroblastic reticular cells (FRCs, ochre) and are filtered through plasmalemma vesicle-associated protein (PLVAP) diaphragms on floor LECs(b); immune complexes and particles are ferried across the SCS by SCS macrophages (Mϕ) (c). The bulk of soluble antigens not retained or channeled in the above compartments pass through to the medullary sinus, where they are sampled by medullary sinus dendritic cells (DCs) prior to draining to the downstream LN via efferent lymphatic vessels (d). Floor and ceiling LECs establish chemokine gradients that guide antigen-bearing migrating DCs arriving from the periphery by differential expression of atypical chemokine receptors, such as CCRL1, that scavenge CCL21 (e). In the parenchyma, soluble antigens channeled in the conduits are sampled by FRCs as well as LN-resident DCs(f) before they reach the high endothelial venules (HEVs, aqua), which are surrounded by FRCs or α7+pericytes (green, part of the double negative DN stromal population), and enter the circulation where they can be sampled by blood endothelial cells (BECs, aqua) (g). Conduits also deliver lower molecular weight antigens to follicular dendritic cells (FDCs, rose) in the B cell follicle(h), while SCS Mϕ relay larger antigens to FDCs or to B cells(i). Antigens on FDCs are available for sampling by DCs and antigen-specific B cells for extended durations. Stromal cells as well as APCs communicate with T cells, contributing to antigen-specific immunological outcomes.
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Figure 1: Exogenous antigen distribution in the lymph node is choreographed by stromal cells. Lymph-borne peripheral exogenous antigens arrive in the lymph node (LN) via the afferent lymphatic vessels as fast-draining soluble or slow arriving cell-associated forms. Floor and ceiling lymphatic endothelial cells (LECs, violet) are the first stromal cells encountered by the antigens in the subcapsular sinus (SCS). Soluble antigens can be taken up and sequestered by LECs(a), while the remaining fraction of antigens leave the SCS: lower molecular weight antigens are channeled to conduits surrounded by fibroblastic reticular cells (FRCs, ochre) and are filtered through plasmalemma vesicle-associated protein (PLVAP) diaphragms on floor LECs(b); immune complexes and particles are ferried across the SCS by SCS macrophages (Mϕ) (c). The bulk of soluble antigens not retained or channeled in the above compartments pass through to the medullary sinus, where they are sampled by medullary sinus dendritic cells (DCs) prior to draining to the downstream LN via efferent lymphatic vessels (d). Floor and ceiling LECs establish chemokine gradients that guide antigen-bearing migrating DCs arriving from the periphery by differential expression of atypical chemokine receptors, such as CCRL1, that scavenge CCL21 (e). In the parenchyma, soluble antigens channeled in the conduits are sampled by FRCs as well as LN-resident DCs(f) before they reach the high endothelial venules (HEVs, aqua), which are surrounded by FRCs or α7+pericytes (green, part of the double negative DN stromal population), and enter the circulation where they can be sampled by blood endothelial cells (BECs, aqua) (g). Conduits also deliver lower molecular weight antigens to follicular dendritic cells (FDCs, rose) in the B cell follicle(h), while SCS Mϕ relay larger antigens to FDCs or to B cells(i). Antigens on FDCs are available for sampling by DCs and antigen-specific B cells for extended durations. Stromal cells as well as APCs communicate with T cells, contributing to antigen-specific immunological outcomes.

Mentions: The lymphatic system represents an efficient and sophisticated mode of communication between peripheral tissues and their draining LNs, with the lymph as its medium. The lymph is composed of a mixture of biomolecules, including proteins, peptides, and exogenously derived antigens that reflect the state of the peripheral tissue. Under normal, physiological conditions, lymph has been shown to be significantly enriched, relative to plasma, in intracellular and extracellular matrix proteins and peptides derived from tissue homeostatic turn-over (42). Human lymph has also been shown to carry a more diverse self-peptidome relative to plasma (43). Hence, the lymph fluid appears to represent a comprehensive status report of the peripheral tissues. Following an infection or an inflammatory challenge, exogenous antigens and self-peptides from damaged cells, together with homeostatic components of lymph, enter tissue-draining LNs. This mixture of antigens, including soluble, particulate, and APC-borne forms, is ushered to different anatomic regions of the LN, notably through the interaction with resident LNSCs (Figure 1).


Modes of Antigen Presentation by Lymph Node Stromal Cells and Their Immunological Implications.

Hirosue S, Dubrot J - Front Immunol (2015)

Exogenous antigen distribution in the lymph node is choreographed by stromal cells. Lymph-borne peripheral exogenous antigens arrive in the lymph node (LN) via the afferent lymphatic vessels as fast-draining soluble or slow arriving cell-associated forms. Floor and ceiling lymphatic endothelial cells (LECs, violet) are the first stromal cells encountered by the antigens in the subcapsular sinus (SCS). Soluble antigens can be taken up and sequestered by LECs(a), while the remaining fraction of antigens leave the SCS: lower molecular weight antigens are channeled to conduits surrounded by fibroblastic reticular cells (FRCs, ochre) and are filtered through plasmalemma vesicle-associated protein (PLVAP) diaphragms on floor LECs(b); immune complexes and particles are ferried across the SCS by SCS macrophages (Mϕ) (c). The bulk of soluble antigens not retained or channeled in the above compartments pass through to the medullary sinus, where they are sampled by medullary sinus dendritic cells (DCs) prior to draining to the downstream LN via efferent lymphatic vessels (d). Floor and ceiling LECs establish chemokine gradients that guide antigen-bearing migrating DCs arriving from the periphery by differential expression of atypical chemokine receptors, such as CCRL1, that scavenge CCL21 (e). In the parenchyma, soluble antigens channeled in the conduits are sampled by FRCs as well as LN-resident DCs(f) before they reach the high endothelial venules (HEVs, aqua), which are surrounded by FRCs or α7+pericytes (green, part of the double negative DN stromal population), and enter the circulation where they can be sampled by blood endothelial cells (BECs, aqua) (g). Conduits also deliver lower molecular weight antigens to follicular dendritic cells (FDCs, rose) in the B cell follicle(h), while SCS Mϕ relay larger antigens to FDCs or to B cells(i). Antigens on FDCs are available for sampling by DCs and antigen-specific B cells for extended durations. Stromal cells as well as APCs communicate with T cells, contributing to antigen-specific immunological outcomes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561840&req=5

Figure 1: Exogenous antigen distribution in the lymph node is choreographed by stromal cells. Lymph-borne peripheral exogenous antigens arrive in the lymph node (LN) via the afferent lymphatic vessels as fast-draining soluble or slow arriving cell-associated forms. Floor and ceiling lymphatic endothelial cells (LECs, violet) are the first stromal cells encountered by the antigens in the subcapsular sinus (SCS). Soluble antigens can be taken up and sequestered by LECs(a), while the remaining fraction of antigens leave the SCS: lower molecular weight antigens are channeled to conduits surrounded by fibroblastic reticular cells (FRCs, ochre) and are filtered through plasmalemma vesicle-associated protein (PLVAP) diaphragms on floor LECs(b); immune complexes and particles are ferried across the SCS by SCS macrophages (Mϕ) (c). The bulk of soluble antigens not retained or channeled in the above compartments pass through to the medullary sinus, where they are sampled by medullary sinus dendritic cells (DCs) prior to draining to the downstream LN via efferent lymphatic vessels (d). Floor and ceiling LECs establish chemokine gradients that guide antigen-bearing migrating DCs arriving from the periphery by differential expression of atypical chemokine receptors, such as CCRL1, that scavenge CCL21 (e). In the parenchyma, soluble antigens channeled in the conduits are sampled by FRCs as well as LN-resident DCs(f) before they reach the high endothelial venules (HEVs, aqua), which are surrounded by FRCs or α7+pericytes (green, part of the double negative DN stromal population), and enter the circulation where they can be sampled by blood endothelial cells (BECs, aqua) (g). Conduits also deliver lower molecular weight antigens to follicular dendritic cells (FDCs, rose) in the B cell follicle(h), while SCS Mϕ relay larger antigens to FDCs or to B cells(i). Antigens on FDCs are available for sampling by DCs and antigen-specific B cells for extended durations. Stromal cells as well as APCs communicate with T cells, contributing to antigen-specific immunological outcomes.
Mentions: The lymphatic system represents an efficient and sophisticated mode of communication between peripheral tissues and their draining LNs, with the lymph as its medium. The lymph is composed of a mixture of biomolecules, including proteins, peptides, and exogenously derived antigens that reflect the state of the peripheral tissue. Under normal, physiological conditions, lymph has been shown to be significantly enriched, relative to plasma, in intracellular and extracellular matrix proteins and peptides derived from tissue homeostatic turn-over (42). Human lymph has also been shown to carry a more diverse self-peptidome relative to plasma (43). Hence, the lymph fluid appears to represent a comprehensive status report of the peripheral tissues. Following an infection or an inflammatory challenge, exogenous antigens and self-peptides from damaged cells, together with homeostatic components of lymph, enter tissue-draining LNs. This mixture of antigens, including soluble, particulate, and APC-borne forms, is ushered to different anatomic regions of the LN, notably through the interaction with resident LNSCs (Figure 1).

Bottom Line: Transfer of antigen between LNSC and dendritic cells in both directions has been recently suggested to promote tolerogenic roles of LNSCs on the CD4(+) T cell compartment.Thus, antigen presentation by LNSCs is thought to be a mechanism that promotes the maintenance of peripheral tolerance as well as generates a pool of diverse antigen-experienced T cells for protective immunity.This review aims to integrate the current and emerging literature to highlight the importance of LNSCs in immune responses, and emphasize their role in antigen trafficking, retention, and presentation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioengineering, École Polytechnique Fédéral de Lausanne , Lausanne , Switzerland.

ABSTRACT
Antigen presentation is no longer the exclusive domain of cells of hematopoietic origin. Recent works have demonstrated that lymph node stromal cell (LNSC) populations, such as fibroblastic reticular cells, lymphatic and blood endothelial cells, not only provide a scaffold for lymphocyte interactions but also exhibit active immunomodulatory roles that are critical to mounting and resolving effective immune responses. Importantly, LNSCs possess the ability to present antigens and establish antigen-specific interactions with T cells. One example is the expression of peripheral tissue antigens, which are presented on major histocompatibility complex (MHC)-I molecules with tolerogenic consequences on T cells. Additionally, exogenous antigens, including self and tumor antigens, can be processed and presented on MHC-I complexes, which result in dysfunctional activation of antigen-specific CD8(+) T cells. While MHC-I is widely expressed on cells of both hematopoietic and non-hematopoietic origins, antigen presentation via MHC-II is more precisely regulated. Nevertheless, LNSCs are capable of endogenously expressing, or alternatively, acquiring MHC-II molecules. Transfer of antigen between LNSC and dendritic cells in both directions has been recently suggested to promote tolerogenic roles of LNSCs on the CD4(+) T cell compartment. Thus, antigen presentation by LNSCs is thought to be a mechanism that promotes the maintenance of peripheral tolerance as well as generates a pool of diverse antigen-experienced T cells for protective immunity. This review aims to integrate the current and emerging literature to highlight the importance of LNSCs in immune responses, and emphasize their role in antigen trafficking, retention, and presentation.

No MeSH data available.


Related in: MedlinePlus