Cutting Edge: Distinct Waves of BCL6 Expression during T Follicular Helper Cell Development

Baumjohann, Dirk; Okada, Takaharu; Ansel, K. Mark

doi:10.4049/jimmunol.1101393

Cited by 195 publications

(248 citation statements)

References 22 publications

Supporting

Mentioning

230

Contrasting

Unclassified

Order By: Relevance

“…These abilities have been associated with an altered expression profile of immunoregulatory receptors (46) and with enhanced abilities for HIV sensing and innate immune recognition (47). However, the impact of DCs from these patients on Tfh development is still unclear, and investigations of DCs on induction of Tfh have mostly been limited to animal studies (11,48,49) or experiments with in vitro generated monocyte-derived DCs (MDDCs) (25,33), rather than primary DCs. To our knowledge, this is the first study to analyze the effects of primary DCs on Tfh priming in a rare group of HIV-1 controllers who are able to generate broader neutralizing breadth in the absence of high-level viral replications.…”

Section: Cxcr3mentioning

confidence: 99%

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

et al. 2017

View full text Add to dashboard Cite

Section: Cxcr3mentioning

confidence: 99%

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

et al. 2017

View full text Add to dashboard Cite

“…The initial Bcl6 induction and subsequent CXCR5 expression allow CD4 T cells to migrate toward the T-B border, where T FH cells interact with antigen-specific B cells. According to this model, cognate B cells are not required for the induction of Bcl6 but support the expansion of T FH cells (9).…”

mentioning

confidence: 99%

Memory B cells contribute to rapid Bcl6 expression by memory follicular helper T cells

Ise

Inoue

McLachlan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

In primary humoral responses, B-cell lymphoma 6 (Bcl6) is a master regulator of follicular helper T (T FH ) cell differentiation; however, its activation mechanisms and role in memory responses remain unclear. Here we demonstrate that survival of CXCR5 + T FH memory cells, and thus subsequent recall antibody response, require Bcl6 expression. Furthermore, we show that, upon rechallenge with soluble antigen Bcl6 in memory T FH cells is rapidly induced in a dendritic cell-independent manner and that peptide:class II complexes (pMHC) on cognate memory B cells significantly contribute to this induction. Given the previous evidence that antigen-specific B cells residing in the follicles acquire antigens within minutes of injection, our results suggest that memory B cells present antigens to the cognate T FH memory cells, thereby contributing to rapid Bcl6 reexpression and differentiation of the T FH memory cells during humoral memory responses.immunological memory | antibody production T he development of high-affinity B-cell memory is essential in most effective vaccines that are in use today. Because most protein antigens require T-cell help to induce B-cell responses, understanding the mechanisms by which memory T and B cells are generated and maintained, as well as how their swift activation is executed, is of fundamental importance for vaccine development.In primary immune responses, it is widely accepted that among several differentiated helper T-cell subsets follicular helper CD4 T cells (T FH cells) are the major subset to deliver help to B cells (1). T FH cells express CXC-chemokine receptor 5 (CXCR5), the chemokine receptor for the B-cell homing chemokine CXCL13. Surface expression of CXCR5 enables T FH cells to migrate into B-cell follicles, where they provide help to B cells to form germinal centers. In addition, T FH cells are needed for the crucial affinitymaturation process of B cells in germinal centers, whereby Agspecific B cells undergo repeated rounds of somatic hypermutation and positive selection by T FH cells to rapidly evolve high-affinity somatically mutated B-cell receptors. B-cell lymphoma 6 (Bcl6) has recently been identified as a T FH lineage regulator (2-4); it is highly expressed by T FH cells and is required for their development. According to the current view, during a primary response Bcl6 expression by T cells is induced by priming with dendritic cells (5-7) and ICOS is a key coreceptor molecule for induction of Bcl6 (5, Although the importance of Bcl6 and its expression kinetics in naïve T-cell differentiation have been well elucidated, its role and activation mechanisms in T FH memory cells still remain obscure. Hence, in this paper we first focus upon the roles of Bcl6, demonstrating its importance for maintenance of T FH memory cells. Then, we show that Bcl6 in memory T FH cells was rapidly induced upon rechallenge with soluble antigen and that this response was mainly mediated through antigen presentation by the cognate memory B cells. Given the good association between Bcl6 wi...

show abstract

“…Further, it has long been known that BCL6 is expressed not only in human B-cell neoplasms, but also in certain T-cell lymphomas (19), which are more recalcitrant to current treatment modalities than are B-cell tumors. Recently the role of BCL6 in T-cell development and function has received increasing attention (20)(21)(22)(23)(24)(25)(26). It is now believed that, even though BCL6 is not required for B or T-cell development, it is absolutely essential for germinal center B-cell (27,28) and T follicular helper cell differentiation (20)(21)(22) and is important in other stages/subsets as well.…”

Section: Discussionmentioning

confidence: 99%

PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas

Baron¹,

Anastasi²,

Hyjek³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Diffuse large B-cell lymphomas in humans are associated with chromosomal rearrangements (∼40%) and/or mutations disrupting autoregulation (∼16%) involving the BCL6 gene. Studies of lymphoma development in humans and mouse models have indicated that lymphomagenesis evolves through the accumulation of multiple genetic alterations. Based on our prior studies, which indicated that carcinogen-induced DNA mutations enhance the incidence of lymphomas in our mouse model expressing a human BCL6 transgene, we hypothesized that mutated genes are likely to play an important cooperative role in BCL6 -associated lymphoma development. We used retroviral insertional mutagenesis in an effort to identify which genes cooperate with BCL6 in lymphomagenesis in our BCL6 transgenic mice. We identified PIM1 as the most frequently recurring cooperating gene in our murine BCL6-associated lymphomas (T- and B-cell types), and we observed elevated levels of PIM1 mRNA and protein expression in these neoplasms. Further, immunohistochemical staining, which was performed in 20 randomly selected BCL6-positive human B- and T-cell lymphomas, revealed concurrent expression of BCL6 and PIM1 in these neoplasms. As PIM1 encodes a serine/threonine kinase, PIM1 kinase inhibition may be a promising therapy for BCL6/PIM1-positive human lymphomas.

show abstract

Cutting Edge: Distinct Waves of BCL6 Expression during T Follicular Helper Cell Development

Cited by 195 publications

References 22 publications

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

Memory B cells contribute to rapid Bcl6 expression by memory follicular helper T cells

PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas

Contact Info

Product

Resources

About