Human secondary lymphoid organs typically contain polyclonally-activated proliferating regulatory T cells

Peters, Jorieke H.; Koenen, Hans J. P. M.; Fasse, Esther; Tijssen, Henk; IJzermans, Jan N.M.; Groenen, Patricia J.T.A.; Schaap, Nicolaas; Kwekkeboom, Jaap; Joosten, Irma

doi:10.1182/blood-2013-03-489443

Cited by 26 publications

(27 citation statements)

References 51 publications

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“…In particular, LN cells displayed a higher CD4/CD8 ratio (5.20 versus 2.33, p = 0.0001), fewer effector memory cells, absent CD8 + T EMRA cells (3.37 6 1.93 in LNCs versus 22.53 6 7.65 in PBMCs, p = 0.01), and markedly increased levels of CD69 on all naive and memory T cell subsets (LNCs: 27.67 6 7.49% versus PBMCs: 3.49 6 2.62%, n = 7, p , 0.0001), which is most likely to represent a retention, rather than activation marker in this tissue. The LN profile seen on aspiration was very consistent with the populations reported in postmortem and surgical samples (26).…”

Section: Discussionsupporting

confidence: 75%

Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery

Tatović

Young

Kochba³

et al. 2015

The Journal of Immunology

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Assessment of immune responses in lymph nodes (LNs) is routine in animals, but rarely done in humans. We have applied minimally invasive ultrasound-guided fine-needle aspiration of the LN to a before-and-after study of the immune response to intradermally delivered Ag in healthy volunteers (n = 25). By comparison with PBMCs from the same individual, LN cells (LNCs) were characterized by reduced numbers of effector memory cells, especially CD8+ TEMRA cells (3.37 ± 1.93 in LNCs versus 22.53 ± 7.65 in PBMCs; p = 0.01) and a marked increased in CD69 expression (27.67 ± 7.49 versus 3.49 ± 2.62%, LNCs and PBMCs, respectively; p < 0.0001). At baseline, there was a striking absence of IFN-γ ELISPOT responses to recall Ags (purified protein derivative, Tetanus toxoid, or flu/EBV/CMV viral mix) in LN, despite strong responses in the peripheral blood. However, 48 h after tuberculin purified protein derivative administration in the ipsilateral forearm resulting in a positive skin reaction, a clear increase in IFN-γ ELISPOT counts was seen in the draining LN but not in PBMCs. This response was lost by 5 d. These data suggest that the low levels of effector memory cells in the LN may explain the low background of baseline ELISPOT responses in LNs as compared with PBMCs, and the appearance of a response after 48 h is likely to represent migration of effector memory cells from the skin to the LN. Hence, it appears that the combination of intradermal Ag administration and draining LN sampling can be used as a sensitive method to probe the effector memory T cell repertoire in the skin.

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Section: Discussionsupporting

confidence: 75%

Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery

Tatović

Young

Kochba³

et al. 2015

The Journal of Immunology

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“…A limitation of our and similar studies (Brodin et al., 2015, Carr et al., 2016, Orrù et al., 2013, Roederer et al., 2015) is that circulating immune cells are used and do not represent the full landscape of human immunity. Strong differences in immune cell composition have been reported between human peripheral blood, bone marrow, spleen, and lymph nodes (Peters et al., 2013). However, obtaining samples of lymphoid organs in a cohort of healthy individuals is not feasible for ethical and practical reasons.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Environmental and Genetic Factors on T and B Cell Immune Traits

et al. 2016

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SummaryEffective immunity requires a complex network of cellular and humoral components that interact with each other and are influenced by different environmental and host factors. We used a systems biology approach to comprehensively assess the impact of environmental and genetic factors on immune cell populations in peripheral blood, including associations with immunoglobulin concentrations, from ∼500 healthy volunteers from the Human Functional Genomics Project. Genetic heritability estimation showed that variations in T cell numbers are more strongly driven by genetic factors, while B cell counts are more environmentally influenced. Quantitative trait loci (QTL) mapping identified eight independent genomic loci associated with leukocyte count variation, including four associations with T and B cell subtypes. The QTLs identified were enriched among genome-wide association study (GWAS) SNPs reported to increase susceptibility to immune-mediated diseases. Our systems approach provides insights into cellular and humoral immune trait variability in humans.

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“…Previous work published by Peters et al [35] suggested that Treg trafficking patterns might be strongly perturbed in solid tumor patients. A potential role of the BM for Treg recirculation in cancer patients has been already suggested by Zhao et al [36].…”

Section: Discussionmentioning

confidence: 99%

Tumor specific regulatory T cells in the bone marrow of breast cancer patients selectively upregulate the emigration receptor S1P1

Rathinasamy

Domschke

et al. 2017

Cancer Immunol Immunother

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Regulatory T cells (Treg) hamper anti-tumor T-cell responses resulting in reduced survival and failure of cancer immunotherapy. Among lymphoid organs, the bone marrow (BM) is a major site of Treg residence and recirculation. However, the process governing the emigration of Treg from BM into the circulation remains elusive. We here show that breast cancer patients harbour reduced Treg frequencies in the BM as compared to healthy individuals or the blood. This was particularly the case for tumor antigen-specific Treg which were quantified by MHCII tumor peptide loaded tetramers. We further demonstrate that decreased Treg distribution in the BM correlated with increased Treg redistribution to tumor tissue, suggesting that TCR triggering induces a translocation of Treg from the BM into tumor tissue. Sphingosine-1-phosphate receptor 1 (S1P1)—which is known to mediate exit of immune cells from lymphoid organs was selectively expressed by tumor antigen-specific BM Treg. S1P1 expression could be induced in Treg by BM-resident antigen-presenting cells (BMAPCs) in conjunction with TCR stimulation, but not by TCR stimulation or BMAPCs alone and triggered the migration of Treg but not conventional T cells (Tcon) to its ligand Sphingosine-1-phosphate (S1P). Interestingly, we detected marked S1P gradients between PB and BM in breast cancer patients but not in healthy individuals. Taken together, our data suggest a role for S1P1 in mediating the selective mobilization of tumor specific Treg from the BM of breast cancer patients and their translocation into tumor tissue.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-017-1964-4) contains supplementary material, which is available to authorized users.

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Human secondary lymphoid organs typically contain polyclonally-activated proliferating regulatory T cells

Abstract: Key Points The majority of suppressive Tregs in human secondary lymphoid organs are activated, produce cytokines, and proliferate. Human lymphoid organs may provide a platform for in vivo expansion of infused Tregs and subsequent tissue-directed homing.

Cited by 26 publications

References 51 publications

Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery

Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery

Differential Effects of Environmental and Genetic Factors on T and B Cell Immune Traits

Tumor specific regulatory T cells in the bone marrow of breast cancer patients selectively upregulate the emigration receptor S1P1

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