B lymphocyte activation upon exclusive recognition of major histocompatibility antigens by T helper cells

CCR9 and α4β7 are the major trafficking receptors for lymphocyte migration to the gut, and their expression is induced during lymphocyte activation under the influence of retinoic acid (RA). We report here that BATF (basic leucine zipper transcription factor, ATF-like), an AP-1 protein family factor, is required for optimal expression of CCR9 and α4β7 by T helper cells. BATF-deficient (knockout [KO]) mice had reduced numbers of effector T and regulatory T cells in the intestine. The intestinal T cells in BATF KO mice expressed CCR9 and α4β7 at abnormally low levels compared with their wild-type (WT) counterparts, and BATF KO CD4+ T cells failed to up-regulate the expression of CCR9 and α4β7 to WT levels in response to RA. Defective binding of RARα and histone acetylation at the regulatory regions of the CCR9 and Itg-α4 genes were observed in BATF KO T cells. As a result, BATF KO effector and FoxP3+ T cells failed to populate the intestine, and neither population functioned normally in the induction and regulation of colitis. Our results establish BATF as a cellular factor required for normal expression of CCR9 and α4β7 and for the homeostasis and effector functions of T cell populations in the intestine.

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Molecular mechanisms for B lymphocyte selection: induction and regulation of antigen-receptor-mediated apoptosis of mature B cells in normal mice and their defect in autoimmunity-prone mice

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1994.0109 ◽

1994 ◽

Vol 345 (1313) ◽

pp. 297-301 ◽

Cited By ~ 11

Keyword(s):

Immune System ◽

B Cells ◽

B Cell ◽

T Helper Cells ◽

Molecular Mechanisms ◽

B Lymphocyte ◽

Antigen Receptor ◽

Normal Function ◽

T Helper ◽

Helper Cells

Apoptosis (programmed cell death) has been suggested to be involved in clonal elimination of selfreactive lymphocytes for the normal function of the immune system. By crosslinking the antigen receptor (surface immunoglobulin; slg) on the peritoneal B cells of normal mice, we found that strong crosslinking of slg induces apoptosis of mature B cells, suggesting that interaction with membranebound self-antigens may eliminate self-reactive mature B cells by apoptosis. Antigen-receptor-mediated B cell apoptosis is blocked when a signal is transduced via the CD40 molecule on the B cell surface. Because the ligand of CD40 (CD40L) is expressed on activated T helper cells, B cells may escape from apoptosis and are activated when the immune system interacts with foreign antigens, which are normally able to activate T helper cells. Moreover, slg crosslinking fails to induce apoptosis of both bcl-2-transgenic mice and autoimmune-disease-prone New Zealand mice. In these mice, the defect in slg-mediated apoptosis of mature B cells may allow generation of self-reactive B cells, resulting in pathogenic consequences.

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INDIСATORS OF THE LYMPHOCYTE SUBSETS AS EFFICICIENCY PREDICTORS OF THERAPY WITH INHIBITORS OF TNFα IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE

Medical Immunology (Russia) ◽

10.15789/1563-0625-2018-5-721-730 ◽

2018 ◽

Vol 20 (5) ◽

pp. 721-730

Author(s):

S. V. Petrichuk ◽

L. V. Miroshkina ◽

E. L. Semikina ◽

A. P. Toptygina ◽

A. S. Potapov ◽

...

Keyword(s):

B Lymphocytes ◽

Therapeutic Effect ◽

T Helper Cells ◽

B Lymphocyte ◽

Comparison Group ◽

Clinical State ◽

Therapeutic Effects ◽

Healthy Children ◽

T Helper ◽

Helper Cells

(IBD), who were for the first time treated with TNFα blocker (infliximab). Our aim was to determine prognostic informative value of the immunological parameters in order to assess the treatment efficiency. A comprehensive research included seventy children with IBD from 12 to 18 years old in the course of specific treatment (49 children with CD, 21 children with UC).The comparison group consisted of fifty healthy children of similar age who were subjected to a similar detailed examination. The patients were divided into two groups, depending on their therapeutic response following 1 year of biological therapy: the first group showed a persistent positive effect of the drug, and the second group exhibited only unstable effects of the treatment. We determined the contents of major and small subpopulations of peripheral blood lymphocytes before the first administration of infliximab. Immunophenotyping was performed by multicolor flow cytometry (FC 500), using the CD45, CD3, CD4, CD8, CD19, CD16, CD56, HLA-DR, CD5, CD161, CD127, CD25, and CD294 markers.We have revealed that the content of B lymphocytes was significantly reduced in children with unstable effects of therapy. By contrast, the B lymphocyte levels in children with persistent positive therapeutic effect did not differ from the comparison group. Analysis of the composition of the B lymphocyte profile showed an imbalance in the B1-to-B2 cell ratio, with decreased of B1 cell counts in IBD patients against the comparison group. In addition, the patients with unstable therapeutic effect showed a significant decrease in B2 cell numbers compared with a group with persistent effect and comparison group. The numbers of NK cells in IBD patients were found to be reduced against the comparison group. Assessment of T lymphocytes subsets revealed a number of features in the patients with minimal therapeutic effects, i.e., an increased level of activated T helper cells (CD4+CD25+CD127high) and Th17 lymphocytes (CD3+CD4+CD161+), as compared to children with stable effect of treatment and to the comparison group. Moreover, in children with minimal effects of therapy, the levels of Tregs within T-helper cell subsets were significantly higher than in the comparison group. By means of ROC analysis, we have identified most informative parameters for the groups with minimal versus persistent therapeutic effect, and showed a good quality for a discrimination model involving relative amount of Th17 cells, activated T helper cells and B lymphocytes. The number of Тh17 lymphocytes (% CD3+CD4+ lymphocytes) allowed to predict the effect of therapy with a TNFα blocker with high probability. The present study enables us to propose cellular immunity testing, as a promising tool for monitoring clinical state of IBD patients.

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