Regulatory T Cells Control Antigen-Specific Expansion of Tfh Cell Number and Humoral Immune Responses via the Coreceptor CTLA-4

SummaryCD4+Foxp3-expressing Treg cells, which constitutively express the inhibitory coreceptor CTLA-4, are indispensable for immune homeostasis. We determined the roles of Treg cells and T follicular regulatory (Tfr) cells in the control of humoral immune responses. Depletion of Treg cells, blocking of CTLA-4 or a Treg cell specific reduction in CTLA-4 expression, resulted in an increase in the formation of antigen-specific Tfh cells, germinal center (GC), and plasma and memory B cells after vaccination. In the absence of Treg cell-expressed CTLA-4, large numbers of Tfr cells were present but were unable to restrain Tfh cell and GC formation. Temporary Treg cell depletion during primary immunization was sufficient to enhance secondary immune responses. Treg cells directly inhibited, via CTLA-4, B cell expression of CD80 and CD86, which was essential for Tfh cell formation. Thus, Treg and Tfr cells control Tfh cell and germinal center development, via CTLA-4-dependent regulation of CD80 and CD86 expression

Alteration of the immune environment in bone marrow from children with recurrent B cell precursor acute lymphoblastic leukemia

Due to the considerable success of cancer immunotherapy for leukemia, the tumor immune environment has become a focus of intense research; however, there are few reports on the dynamics of the tumor immune environment in leukemia. Here, we analyzed the tumor immune environment in pediatric B cell precursor acute lymphoblastic leukemia by analyzing serial bone marrow samples from nine patients with primary and recurrent disease by mass cytometry using 39 immunophenotype markers, and transcriptome analysis. High-dimensional single-cell mass cytometry analysis elucidated a dynamic shift of T cells from naïve to effector subsets, and clarified that, during relapse, the tumor immune environment comprised a T helper 1-polarized immune profile, together with an increased number of effector regulatory T cells. These results were confirmed in a validation cohort using conventional flow cytometry. Furthermore, RNA transcriptome analysis identified the upregulation of immune-related pathways in B cell precursor acute lymphoblastic leukemia cells during relapse, suggesting interaction with the surrounding environment. In conclusion, a tumor immune environment characterized by a T helper 1-polarized immune profile, with an increased number of effector regulatory T cells, could contribute to the pathophysiology of recurrent B cell precursor acute lymphoblastic leukemia. This information could contribute to the development of effective immunotherapeutic approaches against B cell precursor acute lymphoblastic leukemia relapse

The effect of mannose-binding lectin on the cellular interactions of Neisseria gonorrhoeae

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Flow diagram of study selection.

<p>Flow diagram of study selection.</p

Study information about proportion of Tregs in RA patients or control subjects

<p>Study information about proportion of Tregs in RA patients or control subjects</p

Forest plot for sub-group meta-analysis of the proportion of Tregs defined by CD25 and FOXP3 double positive.

<p>Standardized mean difference (the proportion of Tregs among CD4⁺ T cells in PB of RA patients minus that of control subjects) was estimated by meta-analysis. Tregs, which were defined by “CD25 and FOXP3 double positive”, were selected for sub-analysis.</p

Forest plots of the proportion of Tregs in peripheral blood of different diseases activity and synovial fluid.

<p>(A) Standardized mean difference (the proportion of Tregs among CD4⁺ T cells in PB of active RA patients minus that of remission RA patients) was estimated by meta-analysis. Tregs, which were defined by “CD25 and FOXP3 double positive”, were selected for meta-analysis. (B) Standardized mean difference (the proportion of Tregs among CD4⁺ T cells in SF of RA patients minus that in PB of control subjects) was estimated by meta-analysis. Tregs, which were defined by “CD25 and FOXP3 double positive”, were selected for meta-analysis.</p