Peripheral tolerance induced in lymph nodes by syngenic spleen cells inhibits generation of CTLs to hapten-altered self antigens but not to alloantigens

In the attempt to understand the origin of autoantibody (AAb) production in patients with and at-risk for T1D, multiple studies have analyzed and reported alterations in follicular helper T cells (Tfh) in presymptomatic AAb-positive subjects and patients with T1D. Yet, it is still not clear whether the regulatory counterpart of Tfh cells, represented by follicular regulatory T cells (Tfr), is similarly altered. To address this question, we performed analyses in peripheral blood, spleen and pancreatic lymph nodes (PLN) of organ donor subjects with T1D. Blood analyses were also performed in living AAb-negative and -positive subjects. While negligible differences in the frequency and phenotype of blood Tfr cells were observed between T1D, AAb-negative and AAb-positive adult subjects, the frequency of Tfr cells was significantly reduced in spleen and PLN of T1D as compared to non-diabetic controls. Furthermore, adoptive transfer of Tfr cells delayed disease development in a mouse model of T1D, a finding that could indicate that Tfr cells play an important role in peripheral tolerance and regulation of autoreactive Tfh cells. Together, our findings provide evidence of Tfr cell alterations within disease-relevant tissues in patients with T1D suggesting a role for Tfr cells in defective humoral tolerance and disease pathogenesis.

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Fas/FasL Signaling Regulates CD8 Expression During Exposure to Self-Antigens

Frontiers in Immunology ◽

10.3389/fimmu.2021.635862 ◽

2021 ◽

Vol 12 ◽

Author(s):

Giovanna Flores-Mendoza ◽

Noé Rodríguez-Rodríguez ◽

Rosa M. Rubio ◽

Iris K. Madera-Salcedo ◽

Florencia Rosetti ◽

...

Keyword(s):

T Cells ◽

T Cell Activation ◽

Cell Activation ◽

Peripheral Tolerance ◽

Tolerance Mechanism ◽

Genetic Deficiency ◽

Self Antigen ◽

Insight Into ◽

Self Antigens

Activation of self-reactive CD8+ T cells induces a peripheral tolerance mechanism that involves loss of CD8 expression. Because genetic deficiency of Fas and Fasl causes the accumulation of double-negative (DN; CD3+ TCR-αβ+ CD4- CD8-) T cells that have been proposed to derive from CD8+ cells, we decided to explore the role of Fas and FasL in self-antigen-induced CD8 downregulation. To this end, we quantified Fas and FasL induction by different stimuli and analyzed the effects of Fas/FasL deficiency during a protective immune response and after exposure to self-antigens. Our data describes how Fas and FasL upregulation differs depending on the setting of CD8 T cell activation and demonstrates that Fas/FasL signaling maintains CD8 expression during repetitive antigen stimulation and following self-antigen encounter. Together, our results reveal an unexpected role of Fas/FasL signaling and offer a new insight into the role of these molecules in the regulation of immune tolerance.

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Enhancement of LAK-like activity and cytokine induction in regional lymph nodes and spleen cells of mice after intralymphnodal injection of OK-432, a killed streptococcal preparation

Anti-Cancer Drugs ◽

10.1097/00001813-199306000-00016 ◽

1993 ◽

Vol 4 (3) ◽

pp. 381-388 ◽

Cited By ~ 1

Author(s):

Chouhei Sakakura ◽

Toshio Takahashi ◽

Akeo Hagiwara ◽

Tetsuro Yamane ◽

Seiji Sawai ◽

...

Keyword(s):

Lymph Nodes ◽

Spleen Cells ◽

Regional Lymph Nodes ◽

Cytokine Induction ◽

Streptococcal Preparation

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Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells

Blood ◽

10.1182/blood-2011-09-379776 ◽

2012 ◽

Vol 120 (6) ◽

pp. 1237-1245 ◽

Cited By ~ 51

Author(s):

Caterina Vitali ◽

Francesca Mingozzi ◽

Achille Broggi ◽

Simona Barresi ◽

Francesca Zolezzi ◽

...

Keyword(s):

Dendritic Cells ◽

Steady State ◽

Lymph Nodes ◽

Lymphoid Tissue ◽

Essential Role ◽

Peripheral Tolerance ◽

Self Tolerance ◽

Cell Conversion ◽

Itreg Cell ◽

Local Generation

Abstract There is evidence that dendritic cells (DCs) induce peripheral tolerance. Nevertheless, it is not known whether immature DCs in general are able to tolerize CD4+ T cells or if this is a prerogative of specialized subtypes. Here we show that, when autoantigen presentation is extended to all conventional mouse DCs, immature lymphoid tissue resident DCs are unable to induce autoantigen-specific regulatory T (iTreg) cell conversion. In contrast, this is an exclusive prerogative of steady-state migratory DCs. Because only lymph nodes host migratory DCs, iTreg cells develop and are retained solely in lymph nodes, and not in the spleen. Mechanistically, in cutaneous lymph nodes, DC-derived CCL22 contributes to the retention of iTreg cells. The importance of the local generation of iTreg cells is emphasized by their essential role in preventing autoimmunity.

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Single-cell mapping reveals new markers and functions of lymphatic endothelial cells in lymph nodes

10.1101/2020.01.09.900241 ◽

2020 ◽

Cited By ~ 1

Author(s):

Noriki Fujimoto ◽

Yuliang He ◽

Marco D’Addio ◽

Carlotta Tacconi ◽

Michael Detmar ◽

...

Keyword(s):

Endothelial Cells ◽

Immune Responses ◽

Lymph Nodes ◽

Single Cell ◽

Cancer Metastasis ◽

Lymphatic Vessels ◽

Peripheral Tolerance ◽

Lymphatic Endothelial Cells ◽

Subcapsular Sinus ◽

Lymphocyte Egress

ABSTRACTLymph nodes (LNs) are highly organized secondary lymphoid organs that mediate adaptive immune responses to antigens delivered via afferent lymphatic vessels. Lymphatic endothelial cells (LECs) line intranodal lymphatic sinuses and organize lymph and antigen distribution. LECs also directly regulate T cells, mediating peripheral tolerance to self-antigens, and play a major role in many diseases including cancer metastasis. However, little is known about the phenotypic and functional heterogeneity of LN LECs. Using single-cell RNA sequencing, we comprehensively defined the transcriptome of LECs in murine skin-draining LNs, and identified new markers and functions of distinct LEC subpopulations. We found that LECs residing in the subcapsular sinus have an unanticipated function in scavenging of modified LDL and also identified a specific cortical LEC subtype implicated in rapid lymphocyte egress from LNs. Our data provide new insights into the diversity of LECs in murine lymph nodes and a rich resource for future studies into the regulation of immune responses by lymph node LECs.

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Multifunctional Roles of Reticular Fibroblastic Cells: More Than Meets the Eye?

Journal of Immunology Research ◽

10.1155/2014/402038 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

H. G. Alvarenga ◽

L. Marti

Keyword(s):

Immune Response ◽

Lymph Nodes ◽

Stromal Cells ◽

Lymphoid Organ ◽

Peripheral Tolerance ◽

Structural Function ◽

Cytokines And Chemokines ◽

Functional Aspects ◽

Reticular Cells ◽

Fibroblastic Cells

Fibroblastic reticular cells (FRCs) are stromal cells found in secondary lymphoid organ. Despite its structural function in the lymph nodes being well established, recent studies indicate that the FRCs also play a key role in immunological processes, associated with cell transit, immune response, and cells activation quality, and contribute to peripheral tolerance. To this end, we focus this review on lymph nodes FRC characterization and discuss functional aspects such as production of cytokines and chemokines and their involvement in the immune response, seeking to establish whether certain subsets have a more functional specialization.

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Migratory behavior of lymphocytes with specific reactivity to alloantigens. II. Selective recruitment to lymphoid cell allografts and their draining lymph nodes.

Journal of Experimental Medicine ◽

10.1084/jem.147.1.13 ◽

1978 ◽

Vol 147 (1) ◽

pp. 13-24 ◽

Cited By ~ 15

Author(s):

E E Emeson

Keyword(s):

Lymph Nodes ◽

Tumor Immunology ◽

Migratory Behavior ◽

Spleen Cells ◽

Dual Isotope ◽

The Mean ◽

Specific Reactivity ◽

Multiple Groups ◽

The Right ◽

Draining Lymph Nodes

A dual-antigen, dual-isotope assay has been used to monitor the migratory behavior of selectively labeled antiallogeneic lymphocytes in mice challenged subcutaneously in all four foot pads with semiallogeneic spleen cells. 3H-labeled anti-C3H and 14C-labeled anti-C57BL lymphocytes of DBA/2J origin were pooled and adoptively transferred to multiple groups of previously challenged DBA/2J recipients. In some of the studies, separate groups of recipients were challenged with either CDF or BDF spleen cells in all four paws, whereas in others CDF spleen cells were used to challenge the right paws of each mouse in the group and BDF spleen cells to challenge the left paws of each mouse in the group. At intervals varying from 24 to 96 h after challenge, a subgroup of four mice from each appropriate group was sacrificed and the relative numbers of anti-C3H and anti-C57BL lymphocytes present in the challenged paws, draining lymph nodes, and other tissues of each mouse were inferred from the mean 3H/14C ratios of the respective tissues of that subgroup. The results of these studies firmly establish that specific antiallogeneic lymphocytes are selectively recruited to the paws and draining lymph nodes of mice challenged subcutaneously in the foot pads with semiallogeneic spleen cells and are deleted from their circulating blood and nondraining lymph nodes. A mechanism for antigen-induced selective recruitment and its possible functional significance in tumor immunology are discussed.

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