CD80 Expression on B Cells Regulates Murine T Follicular Helper Development, Germinal Center B Cell Survival, and Plasma Cell Generation

Good-Jacobson, Kim L; Song, Eunice; Anderson, Shannon M.; Sharpe, Arlene H.; Shlomchik, Mark J.

doi:10.4049/jimmunol.1102885

Cited by 100 publications

(93 citation statements)

References 51 publications

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“…The simplest explanation for the capacity of T FR to control GC size is that they limit T FH number and thereby restrict the ability of T cells to rescue GC B cells from death. Because T FH homeostasis is tightly linked to the availability of costimulatory ligands on B cells (52,53), it is easy to envisage how T FR could use the CTLA-4 pathway to control T FH by downregulating costimulatory ligand expression on B cells.…”

Section: Discussionmentioning

confidence: 99%

CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

Wang

Heuts

Ovcinnikovs

et al. 2014

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

153

151

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Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an essential regulator of T-cell responses, and its absence precipitates lethal T-cell hyperactivity. However, whether CTLA-4 acts simply to veto the activation of certain clones or plays a more nuanced role in shaping the quality of T-cell responses is not clear. Here we report that T cells in CTLA-4-deficient mice show spontaneous Tfollicular helper (T FH ) differentiation in vivo, and this is accompanied by the appearance of large germinal centers (GCs). Remarkably, short-term blockade with anti-CTLA-4 antibody in wild-type mice is sufficient to elicit T FH generation and GC development. The latter occurs in a CD28-dependent manner, consistent with the known role of CTLA-4 in regulating the CD28 pathway. CTLA-4 can act by down-regulating CD80 and CD86 on antigen presenting cells (APCs), thereby altering the level of CD28 engagement. To mimic reduced CD28 ligation, we used mice heterozygous for CD28, revealing that the magnitude of CD28 engagement is tightly linked to the propensity for T FH differentiation. In contrast, other parameters of T-cell activation, including CD62L down-regulation and Ki67 expression, were relatively insensitive to altered CD28 level. Altered T FH generation as a result of graded reduction in CD28 was associated with decreased numbers of GC B cells and a reduction in overall GC size. These data support a model in which CTLA-4 control of immunity goes beyond vetoing T-cell priming and encompasses the regulation of T FH differentiation by graded control of CD28 engagement.ontrol of the magnitude and nature of adaptive immune responses is critical for health. The cytotoxic T-lymphocyteassociated antigen-4 (CTLA-4)/CD28 axis has long been known to control the magnitude of T-cell responses, however whether it also influences their nature has not been clear. Early studies suggested that CD28 may be particularly important for Th2 differentiation (1, 2), although others identified roles for CD28 in both Th1 and Th2 responses (3, 4). It is known that CD28 is an absolute requirement for the differentiation of follicular helper T cells (T FH s) that support germinal center (GC) formation (5, 6). However, these studies generally make use of CD28-deficient T cells, and therefore, results may reflect a failure of the cells to properly activate, proliferate, or survive, particularly given the known contribution of CD28 to these processes.A key outstanding question is whether CD28 costimulation in vivo is more complex than a binary checkpoint for T-cell priming. It is clear that expression of costimulatory ligands on antigen presenting cells (APCs) fluctuates in response to environmental stimuli, being up-regulated by inflammatory cytokines and TLR agonists and down-regulated by Treg-expressed CTLA-4 (7-11). Thus, variable levels of costimulatory ligands will be available for CD28 binding depending on the microenvironmental context. However, whether this simply alters the number of T cells that achieve the required threshold to commit to a resp...

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Section: Discussionmentioning

confidence: 99%

CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

Wang

Heuts

Ovcinnikovs

et al. 2014

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

153

151

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“…Following their initial generation, Tfr cells may either leave the LN and enter the circulation to become memory Tfr cells242 or migrate into the B‐cell follicles where they interact with B cells and undergo full differentiation into effector Tfr cells 239. Tfr cell differentiation following interaction with both DCs and B cells requires co‐stimulation though CD28 and ICOS, and SAP‐dependent stimulation by B cells 236, 237, 239, 247, 248. CTLA‐4 expression on Tfr cells inhibits their differentiation and maintenance via interaction with CD80/86 on DCs and B cells240, 249; and PD‐1 ligation inhibits both Tfr cell differentiation and their subsequent function 239…”

Section: Regulatory Cell Populations and Their Relationship To Bnab Imentioning

confidence: 99%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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“…CD80 is a ligand for CD28 and CTLA-4 expressed on T cells, and its expression on B cells is critical for a correct development of T-dependent B cell responses. A greater proportion of memory B cells upregulates CD80 expression (27,28). CD73 is a nucleotidase that converts AMP in adenosine, is associated with high frequencies of mutation of the Ig genes, and plays a key role in Ig class switch recombination (28)(29)(30).…”

Section: Ag-specific B Cells Are Expanded In Bone Marrow Pbmc and Lmentioning

confidence: 99%

Oil-in-Water Emulsion MF59 Increases Germinal Center B Cell Differentiation and Persistence in Response to Vaccination

Lofano

Mancini

Salvatore

et al. 2015

The Journal of Immunology

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Induction of persistent protective immune responses is a key attribute of a successful vaccine formulation. MF59 adjuvant, an oil-in-water emulsion used in human vaccines, is known to induce persistent high-affinity functional Ab titers and memory B cells, but how it really shapes the Ag-specific B cell compartment is poorly documented. In this study, we characterized the Ab- and Ag-specific B cell compartment in wild-type mice immunized with HlaH35L, a Staphylococcus aureus Ag known to induce measurable functional Ab responses, formulated with MF59 or aluminum salts, focusing on germinal centers (GC) in secondary lymphoid organs. Taking advantage of single-cell flow cytometry analyses, HlaH35L-specific B cells were characterized for the expression of CD38 and GL-7, markers of memory and GC, respectively, and for CD80 and CD73 activation markers. We demonstrated that immunization with MF59-, but not aluminum salt–adjuvanted HlaH35L, induced expanded Ag-specific CD73+CD80− GC B cells in proximal- and distal-draining lymph nodes, and promoted the persistence of GC B cells, detected up to 4 mo after immunization. In addition to increasing GC B cells, MF59-adjuvanted HlaH35L also increased the frequency of T follicular helper cells. This work extends previous knowledge regarding adaptive immune responses to MF59-adjuvanted vaccines, and, to our knowledge, for the first time an adjuvant used in human licensed products is shown to promote strong and persistent Ag-specific GC responses that might benefit the rational design of new vaccination strategies.

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CD80 Expression on B Cells Regulates Murine T Follicular Helper Development, Germinal Center B Cell Survival, and Plasma Cell Generation

Cited by 100 publications

References 51 publications

CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Oil-in-Water Emulsion MF59 Increases Germinal Center B Cell Differentiation and Persistence in Response to Vaccination

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