scholarly journals B lymphocytes in vivo fail to prime naive T cells but can stimulate antigen-experienced T lymphocytes.

1993 ◽  
Vol 177 (3) ◽  
pp. 679-690 ◽  
Author(s):  
F Ronchese ◽  
B Hausmann
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Class Ii ◽  
T Cell Response ◽  
Scid Mice ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cell Responses

The ability of B cells or macrophages and dendritic cells (DC) to elicit class II-restricted T cell responses in vivo was compared using a mouse chimera model. Severe combined immunodeficient (SCID) mice (H-2d), reconstituted either with T or T+B lymphocytes from (H-2d x H-2b) donors, were immunized subcutaneously with protein antigen (Ag) to induce a class II-restricted T cell response. The frequency and major histocompatibility complex restriction of the resulting Ag-specific T cells were analyzed to establish whether B cells were necessary for the induction of class II-restricted T cell responses, and to determine the cell type on which priming had occurred. The results indicated that: (a) B cells are not necessary for the induction of a class II-restricted T cell response in vivo, as the frequencies of interleukin 2 (IL-2)- or IL-3-secreting T cells induced in the presence or absence of B cells were comparable. (b) Activation of naive T cells requires presentation of Ag on DC; Ag presented only on B cells is not sufficient to elicit a response. No H-2b-restricted, IL-3-secreting cells could in fact be detected in SCID mice reconstituted with naive (H-2d x H-2b) T cells and nonimmune or antigen-primed (H-2d x H-2b) B cells. (c) Previously primed T cells are able to be stimulated by Ag presented by both B cells and DC. H-2b-restricted, IL-3-secreting cells could in fact be readily demonstrated in SCID mice reconstituted with antigen-primed (H-2d x H-2b) T and B cells. Irrespective of whether the T cells were naive or previously activated, B cells were able to respond with an Ag-specific immunoglobulin G response, indicating that B cells were functional and able to present Ag in order to receive specific T cell help. Therefore, it appears that B cells are not necessary and do not participate in the initial priming of T cells; however, Ag presented by B cells can reactivate previously primed T cells. Taken together, these data indicate that during the course of an immune response Ag is first presented to naive T cells via DC, and only subsequently primed T cells can be stimulated by Ag presented by B cells.

A spectrum of biophysical interaction modes between T cells and different antigen-presenting cells during priming in 3-D collagen and in vivo

Blood ◽  
2004 ◽  
Vol 104 (9) ◽  
pp. 2801-2809 ◽  
Author(s):  
Matthias Gunzer ◽  
Carsten Weishaupt ◽  
Anja Hillmer ◽  
Yasmin Basoglu ◽  
Peter Friedl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Antigen Presenting Cells ◽  
Model Systems ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Antigen Presenting ◽  
Activated B Cells

Abstract For activation T cells engage antigen-presenting cells (APCs) in lymphatic tissues. The contact duration and kinetics (static versus dynamic) vary considerably in different model systems; however, it is unclear whether T cells, APCs, or the environment are responsible for the observed discrepancies. Using 3-D collagen matrices as structural scaffold, we directly compared the kinetics of T-cell engagement and activation by functionally major APC types, ie, dendritic cells (DCs) and resting or activated B cells. Resting B cells engaged T cells in long-lived (several hours), adhesive, and leukocyte function-associated antigen-1 (LFA-1)-dependent conjugates in 3-D collagen as well as in intact lymph nodes in vivo. DCs and preactivated B cells, however, supported predominantly dynamic, short-lived (minutes), and sequential contacts to T cells that were dependent on high cytoskeletal activity of the APCs but could not be inhibited by anti-LFA-1 treatment. Naive T cells were most strongly activated by DCs and activated B cells, whereas resting B cells were 100-fold less efficient to induce T-cell proliferation. Thus, in the same 3-D environment, naive T cells respond with a spectrum of different interaction modes dependent on the type and activation state of the APCs. Thereby, more dynamic interaction kinetics is positively correlated with higher T-cell priming efficiency. (Blood. 2004;104: 2801-2809)

scholarly journals An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2

2007 ◽  
Vol 204 (8) ◽  
pp. 1787-1801 ◽  
Author(s):  
Jae-Ho Cho ◽  
Onur Boyman ◽  
Hee-Ok Kim ◽  
Bumsuk Hahm ◽  
Mark P. Rubinstein ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
T Cell Response ◽  
Gradual Transition ◽  
Homeostatic Proliferation ◽  
Naive T Cells ◽  
Effector Cells ◽  
Naïve T Cells

In conditions of T lymphopenia, interleukin (IL) 7 levels rise and, via T cell receptor for antigen–self–major histocompatibility complex (MHC) interaction, induce residual naive T cells to proliferate. This pattern of lymphopenia-induced “homeostatic” proliferation is typically quite slow and causes a gradual increase in total T cell numbers and differentiation into cells with features of memory cells. In contrast, we describe a novel form of homeostatic proliferation that occurs when naive T cells encounter raised levels of IL-2 and IL-15 in vivo. In this situation, CD8+ T cells undergo massive expansion and rapid differentiation into effector cells, thus closely resembling the T cell response to foreign antigens. However, the responses induced by IL-2/IL-15 are not seen in MHC-deficient hosts, implying that the responses are driven by self-ligands. Hence, homeostatic proliferation of naive T cells can be either slow or fast, with the quality of the response to self being dictated by the particular cytokine (IL-7 vs. IL-2/IL-15) concerned. The relevance of the data to the gradual transition of naive T cells into memory-phenotype (MP) cells with age is discussed.

ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 216-223 ◽  
Author(s):  
Elodie Segura ◽  
Carole Nicco ◽  
Bérangère Lombard ◽  
Philippe Véron ◽  
Graça Raposo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Responses ◽  
Class Ii ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cell Responses

Exosomes are secreted vesicles formed in late endocytic compartments. Immature dendritic cells (DCs) secrete exosomes, which transfer functional major histocompatibility complex (MHC)–peptide complexes to other DCs. Since immature and mature DCs induce different functional T-cell responses (ie, tolerance versus priming), we asked whether DC maturation also influenced the priming abilities of their exosomes. We show that exosomes secreted by lipopolysaccharide (LPS)–treated mature DCs are 50- to 100-fold more potent to induce antigen-specific T-cell activation in vitro than exosomes from immature DCs. In vitro, exosomes from mature DCs transfer to B lymphocytes the ability to prime naive T cells. In vivo, only mature exosomes trigger effector T-cell responses, leading to fast skin graft rejection. Proteomic and biochemical analyses revealed that mature exosomes are enriched in MHC class II, B7.2, intercellular adhesion molecule 1 (ICAM-1), and bear little milk-fat globule–epidermal growth factor–factor VIII (MFG-E8) as compared with immature exosomes. Functional analysis using DC-derived exosomes from knock-out mice showed that MHC class II and ICAM-1 are required for mature exosomes to prime naive T cells, whereas B7.2 and MFG-E8 are dispensable. Therefore, changes in protein composition and priming abilities of exosomes reflect the maturation signals received by DCs.

scholarly journals Antigen-independent activation of naive and memory resting T cells by a cytokine combination.

1994 ◽  
Vol 180 (3) ◽  
pp. 1159-1164 ◽  
Author(s):  
D Unutmaz ◽  
P Pileri ◽  
S Abrignani
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Effector Function ◽  
Necrosis Factor Alpha ◽  
Naive T Cells ◽  
Naïve T Cells

We investigated whether human resting T cells could be activated to proliferate and display effector function in the absence of T cell receptor occupancy. We report that combination of interleukin 2 (IL-2), tumor necrosis factor alpha, and IL-6 activated highly purified naive (CD45RA+) and memory (CD45RO+) resting CD4+ T cells to proliferate. Under this condition, memory resting T cells could also display effector function as measured by lymphokine synthesis and help for immunoglobulin production by B cells. This novel Ag-independent pathway of T cell activation may play an important role in vivo in recruiting effector T cells at the site of immune response and in maintaining the clonal size of memory T cells in the absence of antigenic stimulation. Moreover, cytokines can induce proliferation of naive T cells without switch to memory phenotype and this may help the maintenance of the peripheral pool of naive T cells.

Steady-state dendritic cells expressing cognate antigen terminate memory CD8+ T-cell responses

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2091-2100 ◽  
Author(s):  
Tony J. Kenna ◽  
Ranjeny Thomas ◽  
Raymond J. Steptoe
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Steady State ◽  
T Cell ◽  
Developmental Plasticity ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cognate Antigen ◽  
Costimulatory Signals

Antigen stimulation of naive T cells in conjunction with strong costimulatory signals elicits the generation of effector and memory populations. Such terminal differentiation transforms naive T cells capable of differentiating along several terminal pathways in response to pertinent environmental cues into cells that have lost developmental plasticity and exhibit heightened responsiveness. Because these cells exhibit little or no need for the strong costimulatory signals required for full activation of naive T cells, it is generally considered memory and effector T cells are released from the capacity to be inactivated. Here, we show that steady-state dendritic cells constitutively presenting an endogenously expressed antigen inactivate fully differentiated memory and effector CD8+ T cells in vivo through deletion and inactivation. These findings indicate that fully differentiated effector and memory T cells exhibit a previously unappreciated level of plasticity and provide insight into how memory and effector T-cell populations may be regulated.

scholarly journals Immune Responses in Perforin Deficient Mice

2021 ◽  
Author(s):  
◽  
Helen Mary Alys Simkins
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza Infection ◽  
T Cell Responses ◽  
Nkt Cells ◽  
T Cell Response ◽  
Dependent Manner ◽  
Cell Responses

<p>Dendritic cells (DC) play a pivotal role in the initiation of T cell responses and earlier studies have shown that their survival is important for the generation of effective immune responses. Cytotoxic T lymphocytes (CTL) and natural killer T (NKT) cells have been proposed to regulate the survival of antigen presenting DC through their ability to kill cells expressing specific antigen via secretion of perforin, a protein contained in cytotoxic granules. Perforin knockout (PKO) mice generate amplified immune responses to DC immunization, suggesting a link between defective cytotoxicity and increased T cell responses. The studies in this thesis used PKO mice and in vivo models of CD8+T cells and NKT cell immune responses to determine whether CTL and NKT cells eliminate DC in a perforin-dependent manner, and whether DC elimination is a mechanism to regulate T cell responses. During a primary influenza infection C57BL/6 and PKO mice generated a similar influenza specific CD8+ immune response. No significant difference in the percentage of influenza epitope PA224-233 specific T cells was observed between C57BL/6 and PKO mice during a secondary influenza infection, but PKO mice had a significantly reduced T cell response directed towards the dominant influenza epitope, NP366-374. The reduced T cell response in PKO mice was not due to differences in activation or differentiation status of specific T cells compared to C57BL/6 mice. Therefore, the extended DC survival in PKO after secondary influenza viral infection, recently reported by other authors, does not appear to correlate with increased expansion of virus specific CD8+T cells in infected mice. The role of NKT cells in DC elimination was assessed in vivo using the NKT cell ligand a-Galactosylceramide (a-GalCer). Injection of a-GalCer in C57BL/6 mice induced a dramatic decline in the number of splenic CD8+DC. A similar decrease in CD8+DC numbers was observed in PKO mice, suggesting that the mechanism of DC loss did not involve perforinmediated killing. In contrast, treatment with a TNF-a neutralizing antibody substantially reduced the decline in CD8+DC numbers. This reduction in splenic CD8+DC occurred as early as 15 hr after a-GalCer treatment, and did not affect generation of CD8+T cell responses or the ability of a-GalCer treatment to provide tumour protection. Taken together, these results suggest that multiple cells and mechanisms can regulate DC survival in vivo. CTL regulate DC survival in vivo in a perforin-dependent manner, but this does not necessarily affect the magnitude of the resulting immune responses. NKT cells also affect the survival of DC in vivo, but in a perforin-independent, cytokine-dependent manner. These findings provide additional knowledge about the in vivo involvement of perforin in regulating DC survival by CTL and NKT cells and the effects this has on T cell responses.</p>

scholarly journals Immune Responses in Perforin Deficient Mice

2021 ◽  
Author(s):  
◽  
Helen Mary Alys Simkins
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza Infection ◽  
T Cell Responses ◽  
Nkt Cells ◽  
T Cell Response ◽  
Dependent Manner ◽  
Cell Responses

<p>Dendritic cells (DC) play a pivotal role in the initiation of T cell responses and earlier studies have shown that their survival is important for the generation of effective immune responses. Cytotoxic T lymphocytes (CTL) and natural killer T (NKT) cells have been proposed to regulate the survival of antigen presenting DC through their ability to kill cells expressing specific antigen via secretion of perforin, a protein contained in cytotoxic granules. Perforin knockout (PKO) mice generate amplified immune responses to DC immunization, suggesting a link between defective cytotoxicity and increased T cell responses. The studies in this thesis used PKO mice and in vivo models of CD8+T cells and NKT cell immune responses to determine whether CTL and NKT cells eliminate DC in a perforin-dependent manner, and whether DC elimination is a mechanism to regulate T cell responses. During a primary influenza infection C57BL/6 and PKO mice generated a similar influenza specific CD8+ immune response. No significant difference in the percentage of influenza epitope PA224-233 specific T cells was observed between C57BL/6 and PKO mice during a secondary influenza infection, but PKO mice had a significantly reduced T cell response directed towards the dominant influenza epitope, NP366-374. The reduced T cell response in PKO mice was not due to differences in activation or differentiation status of specific T cells compared to C57BL/6 mice. Therefore, the extended DC survival in PKO after secondary influenza viral infection, recently reported by other authors, does not appear to correlate with increased expansion of virus specific CD8+T cells in infected mice. The role of NKT cells in DC elimination was assessed in vivo using the NKT cell ligand a-Galactosylceramide (a-GalCer). Injection of a-GalCer in C57BL/6 mice induced a dramatic decline in the number of splenic CD8+DC. A similar decrease in CD8+DC numbers was observed in PKO mice, suggesting that the mechanism of DC loss did not involve perforinmediated killing. In contrast, treatment with a TNF-a neutralizing antibody substantially reduced the decline in CD8+DC numbers. This reduction in splenic CD8+DC occurred as early as 15 hr after a-GalCer treatment, and did not affect generation of CD8+T cell responses or the ability of a-GalCer treatment to provide tumour protection. Taken together, these results suggest that multiple cells and mechanisms can regulate DC survival in vivo. CTL regulate DC survival in vivo in a perforin-dependent manner, but this does not necessarily affect the magnitude of the resulting immune responses. NKT cells also affect the survival of DC in vivo, but in a perforin-independent, cytokine-dependent manner. These findings provide additional knowledge about the in vivo involvement of perforin in regulating DC survival by CTL and NKT cells and the effects this has on T cell responses.</p>

scholarly journals Designing Strategies to Improve the T Cell  Mediated Immunotherapy of Mouse Tumours.

2021 ◽  
Author(s):  
◽  
Haley Ataera
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Tumour Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Full Potential ◽  
Activation Markers ◽  
Cell Responses

<p>The adoptive transfer of activated dendritic cells (DC) loaded with tumour antigen or tumour specific T cells improves weak anti-tumour responses, however, without treatments to relieve suppression, these therapies will continue to fall short of their full potential. The aim of this thesis was to understand the role of hypoxia-induced increases in adenosine and of CD4+ CD25+ Foxp3+ regulatory T cells (Treg) in the suppression of anti-tumour immune responses and to design strategies to abrogate these mechanisms. These aims were investigated using the B16.OVA murine melanoma model because the OVA specific CD4+ (OTII) and CD8+ (OTI) T cell transgenic mice allowed detailed investigation of Ag specific T cell responses. Recent studies have shown that the inhibition of adenosine signalling in activated CD8+ T cells can improve the anti-tumour activity of these cells. To investigate these findings using the B16.OVA model, tumour-bearing mice were given activated OTI T cells and the adenosine receptor inhibitor caffeine. Caffeine treatment did not improve the anti-tumour response, possibly because this response was suppressed due to the increased frequency of myeloid derived suppressor cells observed in mice that received T cells. To determine whether the defective function of tumour infiltrating DC (TIDC) in tumours is due to suppression by Treg, mice were treated with the anti-CD25 monoclonal antibody PC61 to deplete Treg and challenged with tumours. PC61 treatment caused a delay in tumour growth but did not affect DC frequency, or expression of the DC activation markers CD40, CD86 and MHC II in tumours or lymph nodes. DC function was tested using in vitro and in vivo T cell proliferation assays and was found to be unaffected by PC61 treatment. Studies in RAG1-/- mice, which lack Treg, also showed no improvement in DC activation status or function. These results show that Treg do not suppress TIDC in the B16.OVA model. It is well known, however, that Treg suppress T cell responses and it has been suggested that Treg may mediate some of this suppression by using the perforin-granzyme pathway to cause T cell death. To investigate this possibility, naive, perforin sufficient OTI T cells were transferred into normal and perforin knockout (PKO) mice, with or without PC61 treatment. To stimulate an OTI T cell response, mice also received OVA-loaded DC. Depletion of both normal and PKO Treg resulted in decreased death and increased proliferation of the transferred cells, increased expression of IFN-y and TNF-a, and improved in vivo target cell killing by the transferred cells. These findings indicate that perforin expression by Treg is not required to suppress T cell responses or cause T cell death. In conclusion, the results of this thesis were consistent with the observation that there are multiple suppressive mechanisms in tumours and that there is substantial redundancy of these mechanisms. Depletion of Treg was found to improve the anti-tumour response, however, suppression of the DC was still evident, demonstrating that the neutralisation of a single suppressive mechanism may not be sufficient to treat aggressive, late stage cancers such as melanoma.</p>

scholarly journals Antigen-dependent and -independent Ca2+ Responses Triggered in T Cells by Dendritic Cells Compared with B Cells

1998 ◽  
Vol 188 (8) ◽  
pp. 1473-1484 ◽  
Author(s):  
Jérôme Delon ◽  
Nadège Bercovici ◽  
Graça Raposo ◽  
Roland Liblau ◽  
Alain Trautmann
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Mhc Class Ii ◽  
Ex Vivo ◽  
Cell Formation ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Survival Signal

Dendritic cells (DCs) are much more potent antigen (Ag)-presenting cells than resting B cells for the activation of naive T cells. The mechanisms underlying this difference have been analyzed under conditions where ex vivo DCs or B cells presented known numbers of specific Ag–major histocompatibility complex (MHC) complexes to naive CD4+ T cells from T cell antigen receptor (TCR) transgenic mice. Several hundred Ag–MHC complexes presented by B cells were necessary to elicit the formation of a few T–B conjugates with small contact zones, and the resulting individual T cell Ca2+ responses were all-or-none. In contrast, Ag-specific T cell Ca2+ responses can be triggered by DCs bearing an average of 30 Ag–MHC complexes per cell. Formation of T–DC conjugates is Ag-independent, but in the presence of the Ag, the surface of the contact zone increases and so does the amplitude of the T cell Ca2+ responses. These results suggest that Ag is better recognized by T cells on DCs essentially because T–DC adhesion precedes Ag recognition, whereas T–B adhesion requires Ag recognition. Surprisingly, we also recorded small Ca2+ responses in T cells interacting with unpulsed DCs. Using DCs purified from MHC class II knockout mice, we provide evidence that this signal is mostly due to MHC–TCR interactions. Such an Ag-independent, MHC-triggered calcium response could be a survival signal that DCs but not B cells are able to deliver to naive T cells.

Antigen-Pulsed, Interleukin-4-Treated B Cells Activate Primed T Cells In Vitro but not Naive T Cells In Vivo

1995 ◽  
Vol 42 (5) ◽  
pp. 517-523 ◽  
Author(s):  
R. GRAINGER ◽  
D. N. J. HART ◽  
J. D. WATSON ◽  
M. A. BAIRD
Keyword(s):  
T Cells ◽  
B Cells ◽  
Interleukin 4 ◽  
Naive T Cells ◽  
Naïve T Cells
Sign in / Sign up

Export Citation Format

Share Document