Human T-follicular helper and T-follicular regulatory cell maintenance is independent of germinal centers

Wallin, Elizabeth; Jolly, Elaine C.; Suchánek, Ondřej; Bradley, J. Andrew; Espéli, Marion; Jayne, David; Linterman, Michelle A.; Smith, Kenneth G. C.

doi:10.1182/blood-2014-07-585976

Cited by 106 publications

(98 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with this, a recent mouse study (31) reported that circulating T FR are a long-lived memory population that homes to GC after reactivation. A human study showed that follicular T cell populations do not need an ongoing GC response for their maintenance because treatment with rituximab, known to eliminate GC B cells, had no effect on the follicular T cell compartment (32). Together all these data indicate that circulating T FR are a distinct effector memory population that persists for a long time and is able to recirculate to the lymph nodes when needed.…”

Section: Discussionmentioning

confidence: 99%

Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis

Dhaeze

Peelen

Hombrouck

et al. 2015

The Journal of Immunology

111

134

View full text Add to dashboard Cite

Follicular regulatory T cells (TFR) have been extensively characterized in mice and participate in germinal center responses by regulating the maturation of B cells and production of (auto)antibodies. We report that circulating TFR are phenotypically distinct from tonsil-derived TFR in humans. They have a lower expression of follicular markers, and display a memory phenotype and lack of high expression of B cell lymphoma 6 and ICOS. However, the suppressive function, expression of regulatory markers, and FOXP3 methylation status of blood TFR is comparable with tonsil-derived TFR. Moreover, we show that circulating TFR frequencies increase after influenza vaccination and correlate with anti-flu Ab responses, indicating a fully functional population. Multiple sclerosis (MS) was used as a model for autoimmune disease to investigate alterations in circulating TFR. MS patients had a significantly lower frequency of circulating TFR compared with healthy control subjects. Furthermore, the circulating TFR compartment of MS patients displayed an increased proportion of Th17-like TFR. Finally, TFR of MS patients had a strongly reduced suppressive function compared with healthy control subjects. We conclude that circulating TFR are a circulating memory population derived from lymphoid resident TFR, making them a valid alternative to investigate alterations in germinal center responses in the context of autoimmune diseases, and TFR impairment is prominent in MS.

show abstract

Section: Discussionmentioning

confidence: 99%

Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis

Dhaeze

Peelen

Hombrouck

et al. 2015

The Journal of Immunology

111

134

View full text Add to dashboard Cite

show abstract

“…[29][30][31][32][33] However, several studies have shown that rituximab therapy effectively eliminates B cells from the peripheral blood but fails to effectively deplete all B cells within secondary lymphoid tissues. [34][35][36][37][38][39] Thus, whether PCs remaining in this setting are long-lived or dependent on replenishment by the residual B cells is unknown.…”

Section: Discussionmentioning

confidence: 99%

Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy

Bhoj

Arhontoulis

Wertheim

et al. 2016

Blood

221

160

View full text Add to dashboard Cite

• CD19-targeted T-cell immunotherapy reveals that a population of PCs lacking CD19 expression survives long-term, independent of B cells.• Preexisting humoral immunity to vaccine-related antigens can persist in patients despite marked B-cell aplasia after CTL019 immunotherapy.The mechanisms underlying the maintenance of long-lasting humoral immunity are not well understood. Studies in mice indicate that plasma cells (PCs) can survive up to a lifetime, even in the absence of regeneration by B cells, implying the presence of longlived PCs as a mechanism for long-lasting immunity. Evidence from humans treated with anti-CD20, which depletes circulating B cells, also suggests B-cell-independent longterm survival of some PCs. On the other hand, antibody responses may be sustained solely by short-lived PCs with repopulation from clonally related memory B cells. To explore PC longevity and humoral immunity in humans, we investigated the fate of PCs and their antibodies in adult and pediatric patients who received chimeric antigen receptor-based adoptive T-cell immunotherapy targeting CD19 to treat B-cell lineage malignancies (CTL019). Treatment with CTL019 is frequently associated with B-cell aplasia that can persist for years. Serum antibody titers to vaccine-related antigens were measured, and quantitative assessment of B cells and PCs in blood and bone marrow was performed at various time points before and after CTL019 therapy. While total serum immunoglobulin concentrations decline following CTL019-induced B-cell aplasia, several vaccine/pathogen-specific serum immunoglobulin G and A (IgG and IgA) titers remain relatively stable for at least 6 and 12 months posttreatment, respectively. Analysis of bone marrow biopsies after CTL019 revealed 8 patients with persistence of antibody-secreting PCs at least 25 months post-CTL019 infusion despite absence of CD19 1 CD20 1 B cells. These results provide strong evidence for the existence of memory B-cell-independent, long-lived PCs in humans that contribute to long-lasting humoral immunity. (Blood. 2016;128(3):360-370)

show abstract

“…143 In HIV-1 infection, an increased frequency of Tfr cells in lymph nodes and spleens (as well as in the peripheral blood), suggests Tfr-cell expansion is induced by antigen persistence. So far, it has been shown that, Tfr cells in human lymph nodes do not require B cells for their maintenance, as depletion of CD20 + B cells by rituximab did not decrease the number of CD57 + CXCR5 + Foxp3 + CD127 − Tfr cells.…”

Section: Tfr Cells In Human Lymphoid Organsmentioning

confidence: 99%

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

Fonseca

Ribeiro

Graça

2019

Immunological Reviews

View full text Add to dashboard Cite

Summary Germinal centers (GC) have been known as key anatomic structures in humoral immunity, where isotype switching and affinity maturation occur. As a consequence, elucidation of GC regulation has potential implications for the understanding of autoantibody‐mediated diseases. It is now accepted that different regulatory mechanisms coexist, including the action of a specialized population of Foxp3+ regulatory T cells with unique access to the B‐cell follicle: the T follicular regulatory (Tfr) cells. Tfr cells develop through a multistep process requiring migration through different compartments of lymphoid tissues. This review discusses the ontogeny and physiology of Tfr cells, their distribution within distinct anatomic compartments, and their function. A greater understanding of Tfr biology and GC regulation is likely to lead to better stratification of patients with autoantibody‐mediated diseases, and to the identification of novel therapeutic targets.

show abstract

Human T-follicular helper and T-follicular regulatory cell maintenance is independent of germinal centers

Cited by 106 publications

References 64 publications

Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis

Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis

Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

Contact Info

Product

Resources

About