Early simultaneous production of intranodal CD4 Th2 effectors and recirculating rapidly responding central‐memory‐like CD4 T cells

Serre, Karine; Mohr, Elodie; Toellner, Kai‐Michael; Cunningham, Adam F.; Bird, Roger; Khan, Mahmood; MacLennan, Ian C. M.

doi:10.1002/eji.200838922

Cited by 8 publications

(19 citation statements)

References 58 publications

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“…AFC numbers generated in the response of OTII cell chimeras to alumOVA has previously been shown to peak 7 d after immunization (11). As expected (1,11,31) the response assisted by OTII cells alone predominantly induced switching to IgG1 (Fig. 2B).…”

Section: Cd8 T Cellssupporting

confidence: 71%

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IFN-γ produced by CD8 T cells induces T-bet–dependent and –independent class switching in B cells in responses to alum-precipitated protein vaccine

Mohr

Cunningham

Toellner

et al. 2010

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

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Alum-precipitated protein (alum protein) vaccines elicit long-lasting neutralizing antibody responses that prevent bacterial exotoxins and viruses from entering cells. Typically, these vaccines induce CD4 T cells to become T helper 2 (Th2) cells that induce Ig class switching to IgG1. We now report that CD8 T cells also respond to alum proteins, proliferating extensively and producing IFN-γ, a key Th1 cytokine. These findings led us to question whether adoptive transfer of antigen-specific CD8 T cells alters the characteristic CD4 Th2 response to alum proteins and the switching pattern in responding B cells. To this end, WT mice given transgenic ovalbumin (OVA)-specific CD4 (OTII) or CD8 (OTI) T cells, or both, were immunized with alum-precipitated OVA. Cotransfer of antigen-specific CD8 T cells skewed switching patterns in responding B cells from IgG1 to IgG2a and IgG2b. Blocking with anti-IFN-γ antibody largely inhibited this altered B-cell switching pattern. The transcription factor T-bet is required in B cells for IFN-γ-dependent switching to IgG2a. By contrast, we show that this transcription factor is dispensable in B cells both for IFN-γ-induced switching to IgG2b and for inhibition of switching to IgG1. Thus, T-bet dependence identifies distinct transcriptional pathways in B cells that regulate IFN-γ-induced switching to different IgG isotypes.

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Section: Cd8 T Cellssupporting

confidence: 71%

“…Although OTI cells produced IFN-γ protein (Fig. 1B, Left), as expected (1,11,31), in those chimeras with OTII cells alone, very few of the OTII cells produced IFN-γ (Fig. 1B, Right).…”

Section: Cd8 T Cellssupporting

confidence: 60%

IFN-γ produced by CD8 T cells induces T-bet–dependent and –independent class switching in B cells in responses to alum-precipitated protein vaccine

Mohr

Cunningham

Toellner

et al. 2010

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

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“…Molecules of a similar size are able to disperse rapidly throughout the host and prime in multiple sites (43), and this explains why T cell activation and proliferation was synchronous after sFliC. In contrast, alum-precipitated proteins given s.c. tend to prime in draining LN, but not necessarily in other sites (44)(45)(46).…”

Section: Discussionmentioning

confidence: 95%

Systemic Flagellin Immunization Stimulates Mucosal CD103+ Dendritic Cells and Drives Foxp3+ Regulatory T Cell and IgA Responses in the Mesenteric Lymph Node

Flores‐Langarica

Marshall

Hitchcock

et al. 2012

The Journal of Immunology

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Mucosal immunity is poorly activated after systemic immunization with protein Ags. Nevertheless, induction of mucosal immunity in such a manner would be an attractive and simple way to overcome the intrinsic difficulties in delivering Ag to such sites. Flagellin from Salmonella enterica serovar Typhimurium (FliC) can impact markedly on host immunity, in part via its recognition by TLR5. In this study, we show that systemic immunization with soluble FliC (sFliC) drives distinct immune responses concurrently in the mesenteric lymph nodes (MLN) and the spleen after i.p. and s.c. immunization. In the MLN, but not the spleen, sFliC drives a TLR5-dependent recruitment of CD103+ dendritic cells (DCs), which correlates with a diminution in CD103+ DC numbers in the lamina propria. In the MLN, CD103+ DCs carry Ag and are the major primers of endogenous and transgenic T cell priming. A key consequence of these interactions with CD103+ DCs in the MLN is an increase in local regulatory T cell differentiation. In parallel, systemic sFliC immunization results in a pronounced switching of FliC-specific B cells to IgA in the MLN but not elsewhere. Loss of TLR5 has more impact on MLN than splenic Ab responses, reflected in an ablation of IgA, but not IgG, serum Ab titers. Therefore, systemic sFliC immunization targets CD103+ DCs and drives distinct mucosal T and B cell responses. This offers a potential “Trojan horse” approach to modulate mucosal immunity by systemically immunizing with sFliC.

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“…This could also be envisioned as a migration phenotype whereby long-lived memory precursors potentially seek sites of low antigen stimulation, or resist re-activation in other ways, such as inhibition of antigen-receptor signaling. Supporting this concept, Serre et al have shown that early Tcm recirculate [248]. …”

Section: The Elusive Source Of Effector Memory T Cellsmentioning

confidence: 99%

Early Decision: Effector and Effector Memory T Cell Differentiation in Chronic Infection

Opata¹,

Stephens²

2014

CIR

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As effector memory T cells (Tem) are the predominant population elicited by chronic parasitic infections, increasing our knowledge of their function, survival and derivation, as phenotypically and functionally distinct from central memory and effector T cells will be critical to vaccine development for these diseases. In some infections, memory T cells maintain increased effector functions, however; this may require the presence of continued antigen, which can also lead to T cell exhaustion. Alternatively, in the absence of antigen, only the increase in the number of memory cells remains, without enhanced functionality as central memory. In order to understand the requirement for antigen and the potential for longevity or protection, the derivation of each type of memory must be understood. A thorough review of the data establishes the existence of both memory (Tmem) precursors and effector T cells (Teff) from the first hours of an immune response. This suggests a new paradigm of Tmem differentiation distinct from the proposition that Tmem only appear after the contraction of Teff. Several signals have been shown to be important in the generation of memory T cells, such as the integrated strength of “signals 1-3” of antigen presentation (antigen receptor, co-stimulation, cytokines) as perceived by each T cell clone. Given that these signals integrated at antigen presentation cells have been shown to determine the outcome of Teff and Tmem phenotypes and numbers, this decision must be made at a very early stage. It would appear that the overwhelming expansion of effector T cells and the inability to phenotypically distinguish memory T cells at early time points has masked this important decision point. This does not rule out an effect of repeated stimulation or chronic inflammatory milieu on populations generated in these early stages. Recent studies suggest that Tmem are derived from early Teff, and we suggest that this includes Tem as well as Tcm. Therefore, we propose a testable model for the pathway of differentiation from naïve to memory that suggests that Tem are not fully differentiated effector cells, but derived from central memory T cells as originally suggested by Sallusto et al. in 1999, but much debated since.

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Early simultaneous production of intranodal CD4 Th2 effectors and recirculating rapidly responding central‐memory‐like CD4 T cells

Cited by 8 publications

References 58 publications

IFN-γ produced by CD8 T cells induces T-bet–dependent and –independent class switching in B cells in responses to alum-precipitated protein vaccine

IFN-γ produced by CD8 T cells induces T-bet–dependent and –independent class switching in B cells in responses to alum-precipitated protein vaccine

Systemic Flagellin Immunization Stimulates Mucosal CD103+ Dendritic Cells and Drives Foxp3+ Regulatory T Cell and IgA Responses in the Mesenteric Lymph Node

Early Decision: Effector and Effector Memory T Cell Differentiation in Chronic Infection

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