Immunologic Recovery after Nonmyeloablative (NM) Conditioning: A Comparison between Related Versus Unrelated Donor Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1402-1402 ◽  
Author(s):  
Frederic Baron ◽  
M. Maris ◽  
J. Storek ◽  
M. Metcalf ◽  
K. White ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Infectious Complications ◽  
T Helper ◽  
Helper Cells ◽  
Cmv Reactivation

Abstract Background. After NM conditioning, recipients of peripheral blood stem cells (PBSC) from HLA-identical siblings (MRD) have persistent recipient-derived immunity leading to lower incidence of early infectious complications in comparison with patients (pts) given myeloablative conditioning (Exp Hematol31: 941, 2003). Because of greater genetic disparities, intensity and duration of postgrafting immunosuppression (IS) have been increased in pts given PBSC from HLA-matched unrelated donors (URD), in order to both promote engraftment and decrease risk of GVHD. This study was done to determine how this increased/extended postgrafting IS affected immune recovery and infectious complications. Methods. We compared immunologic recovery in 51 pts given PBSC from MRD (n=51) and 43 pts given grafts from URD after 2 Gy TBI +/− fludarabine. Postgrafting IS concisted of mycophenolate mofetil (MMF, given TID for 40 days followed by a 56 day taper in URD recipients, and BID for 28 days in MRD recipients) and cyclosporin. The counts of blood mononuclear cell subsets were assessed by flow cytometry; frequency of CMV-specific CD4 T-helper cells among CMV seropositive pts or CMV-seronegative pts with CMV-seropositive donors was determined by lymphoproliferation (LPR), limiting-dilution assays (LDA), and intracellular interferon-gamma (IF) production (ICC). Analyses were performed on days 30, 80, 180 and 365 after HCT. Results. On day 30 after HCT, URD recipients had lower counts of total B-cells (P=.02), naive B-cells (P=.03), memory B-cells (P=.01), CD4 T-cells (P=.06), naive CD4 T-cells (P=.05), memory CD4 T-cells (P=.003), CD8 T-cells (P=.0004), naive CD8 T-cells (P=.08) and memory CD8 T-cells (P=.006) than MRD recipients. However, the counts of mononuclear cell subsets were similar in URD and MRD recipients from day 30 to day 365 after HCT. Similarly, the frequency of CMV-specific T-helper cells was significantly lower in URD than in MRD recipients on day 30 after HCT as determined by LPR (median CPM 17 versus 92 per 1000 CD4 T-cells, P=.02), LDA (median 22307 versus 73251 CMV-CD4 T-helper cells per L, P=.7) and ICC (median 0.26% versus 0.93% CD4 cells positive for IF, P=.02). This delay in CMV-specific immune reconstitution translated into increased frequency of CMV-reactivation (and increased use of preemptive antiviral therapy [PET]) among CMV-seropositive pts or CMV-seronegative pts with CMV seropositive donors given URD grafts (63%) compared with MRD (33%) recipients (P=.02) the first 100 days after HCT. This did not lead to increased CMV disease among URD recipients (1 episode) compared with MRD recipients (1 episode), demonstrating that PET was similarly effective in preventing CMV diseases in both groups. After day 100, there were no statistically significant differences in immune reconstitution parameters. Incidence figures for non-CMV viral infections, bacteremias, and invasive fungal infections were not significantly different between the 2 groups. A multivariate analysis assessing pre-transplant and post-transplant factors associated with immunologic recovery after NM conditioning will be presented. Conclusions. Despite similar NM conditioning regimens, immunologic recovery was delayed among URD recipients in comparison to MRD recipients, probably because of increased/extended postgrafting IS. This led to increased incidence of CMV reactivation among URD recipients. CMV infection and immune reconstitution pattern appear similar to those seen after myeloablative PBSC transplantation.

scholarly journals An idiotype-specific helper population that bears immunoglobulin, Ia, and Lyt-1 determinants.

1984 ◽  
Vol 159 (4) ◽  
pp. 1189-1200 ◽  
Author(s):  
D H Sherr ◽  
M E Dorf
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cell Population ◽  
T Helper Cells ◽  
T Helper ◽  
Phenotypic Characteristics ◽  
Surface Phenotype ◽  
Specific Recognition ◽  
Helper Cells ◽  
Helper Activity

A helper cell population with phenotypic characteristics of both B and T cells is described. This helper population, called BH, is present in normal unprimed C57BL/6 mice and preferentially helps the expression of NPb idiotype-bearing plaque-forming B cells in the absence of T helper cells. Its surface phenotype is Lyt-1.2+, Ig+, Lyb-3+, Thy-1.2-, Lyt-2.2-. The helper activity of the BH population is IgH restricted and BH cells selectively bind NPb idiotypic determinants. Collectively the data demonstrate that this unique subpopulation can regulate the response of antibody-secreting B cells through specific recognition of idiotypic determinants.

Virus-Specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-Helper Cells in Patients With Acute and Chronic HCV Infections

2016 ◽  
Vol 150 (3) ◽  
pp. 696-706.e3 ◽  
Author(s):  
Bijan Raziorrouh ◽  
Kathrin Sacher ◽  
Rajiv G. Tawar ◽  
Florian Emmerich ◽  
Christoph Neumann-Haefelin ◽  
...  
Keyword(s):  
T Cells ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
T Helper ◽  
Phenotypic Characteristics ◽  
Helper Cells ◽  
Chronic Hcv ◽  
Follicular T Helper Cells

Activation of DR3 Signaling Expands Recipient Derived Regulatory T Cells and Enhances Donor Immune Reconstitution Derived from Allogeneic Hematopoietic Stem Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1087-1087
Author(s):  
Hidekazu Nishikii ◽  
Byung Su Kim ◽  
Antonio Pierini ◽  
Jeanette Baker ◽  
Dominik Schneidawind ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Hematopoietic Stem ◽  
Hsc Transplantation

Abstract CD4+ Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells which regulate the immune system, maintain the tolerance of self-antigens and enhance immune tolerance after transplantation. It was also reported that recipient derived Treg could provide immune privilege to allogeneic stem cells (HSC) after transplantation. However, the precise interaction with Treg and HSC has not been fully elucidated. In this study, we investigated the role of recipient derived Treg in the engraftment and immune reconstitution following transplantation of purified allogeneic HSC and the effectiveness of Treg expansion following activation of DR3 (Death receptor 3, also called as TNFRSF25) signaling in this model. 　We first tested the effect of Treg depletion using Foxp3-DTR mice in allogeneic HSC transplantation. In this system, FACS-sorted purified HSC (Lin-cKit+Sca1+ population) derived from WT-FVB mice (CD45.1+/H2kq+) were injected into lethally irradiated B6-Foxp3-DTR mice (CD45.2+/H2kb+) with or without pre-treatment of diphtheria toxin (DT). On day 0 and day 28 after transplantation decreased frequencies of Foxp3+ cells in residual recipient derived CD4+ T cells were observed in peripheral blood from the DT treated mice (P<0.001 on day 0, P<0.002 on day 28). Although total myeloid chimerism was comparable between control and DT-treated mice, the frequency of donor derived immune cells including CD4+ T cells (P<0.01 on day 56), CD8+ T cells (P<0.01 on day 56), and B220+ B cells (P<0.001 on day 56) was significantly decreased in DT-treated mice. These data suggested that recipient derived Treg play an important role in allogeneic immune reconstitution after transplantation. DR3 is a member of the TNF receptor superfamily and we previously reported the expansion of Treg by the activation of this signaling pathway (Kim et al, ASH abstract 2013). We next tested whether activation of DR3 signaling by its agonistic antibody would affect the donor immune reconstitution after allogeneic HSC transplantation. The frequencies of Foxp3+ cells in CD4+ T cells were significantly increased in thymus, spleen, peripheral blood, and bone marrow 4 days after antibody injection (P<0.01). Isolated Treg derived from antibody treated mice showed stronger suppressive function in the mixed lymphoid reaction compared with those from isotype antibody treated mice. The mice treated with antibody on day -4 were transplanted with purified allogeneic HSC on day 0. Antibody treated mice showed a higher frequency of donor derived CD4+ T cells (P<0.001 on day 28), CD8+ T cells (P<0.05 on day 28), and B220+ B cells (P<0.05 on day 28) in this allogeneic HSC transplantation model. In summary, our data suggest that recipient derived CD4+Foxp3+ Treg play an important role in donor immune reconstitution and the activation of DR3 signaling in recipient mice enhances donor immune reconstitution by expansion of recipient derived Treg. H.N and BS-K contributed equally to this work. Disclosures No relevant conflicts of interest to declare.

scholarly journals Authentic T helper CD4 (W3/25) antigen on rat peritoneal macrophages.

1985 ◽  
Vol 162 (1) ◽  
pp. 117-127 ◽  
Author(s):  
W A Jefferies ◽  
J R Green ◽  
A F Williams
Keyword(s):  
Molecular Weight ◽  
Monoclonal Antibody ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cells ◽  
T Helper Cells ◽  
Peritoneal Macrophages ◽  
T Helper ◽  
Helper Cells

The rat W3/25 antigen that appears to be equivalent to human CD4 (T4) antigen is expressed on thymocytes and T helper cells and plays a role in the response of T helper cells to antigen. The W3/25 and anti-T4 antibodies also label macrophages. In this paper we examine whether the macrophage antigen is the same as that on T cells. New monoclonal antibodies against the rat CD4 antigen, MRC OX-35 through OX-38, are described, all of which label peritoneal macrophages from normal and athymic rats. The molecular weight of W3/25 antigen on macrophages is indistinguishable from that on T cells. We conclude that macrophages express authentic CD4 (W3/25) antigen. Another new monoclonal antibody, MRC OX-34, labels an antigen of 50-54,000 mol wt that is expressed on rat T but not B cells or peritoneal macrophages. It was used to control for the presence of any T cell products in immunoprecipitation from rat macrophage extracts.

Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 1924-1931 ◽  
Author(s):  
Svenja Hardtke ◽  
Lars Ohl ◽  
Reinhold Förster
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Helper Cells ◽  
Cell Area ◽  
T Helper ◽  
Helper Cells ◽  
Follicular T Helper Cells ◽  
Cell Follicle

Abstract The production of high-affinity antibodies to T-dependent antigens requires the interaction of B cells and T helper cells expressing receptors specific for the same antigen. Although several mechanisms have been elucidated that regulate B-cell trafficking within lymphoid organs, less is known about molecular cues that guide the small subpopulation of CD4+ follicular T helper cells to B-cell follicles. Using adoptive transfer of transgenic T cells in mice, we demonstrate that antigen-induced activation leads to a finely tuned positioning of T cells either to the T-cell area or the B-cell follicle. We show that expression of CXCR5 is indispensable for T cells to enter B-cell follicles, whereas expression of CCR7 provides a counteracting signal to retain activated T cells in the T-cell area. Although only few T cells transiently migrate from the T-cell area to the B-cell follicle of peripheral lymph nodes following antigenic challenge, this step is essential to provide the help B cells require to produce antibodies efficiently. Thus, we demonstrate that the balanced expression of CCR7 and CXCR5 determines the positioning and proper function of follicular T helper cells.

scholarly journals Treg-Resistant Cytotoxic CD4+ T Cells Dictate T Helper Cells in Their Vicinity: TH17 Skewing and Modulation of Proliferation

2021 ◽  
Vol 22 (11) ◽  
pp. 5660
Author(s):  
Cindy Hoeks ◽  
Marjan Vanheusden ◽  
Liesbet M. Peeters ◽  
Piet Stinissen ◽  
Bieke Broux ◽  
...  
Keyword(s):  
T Cells ◽  
Conditioned Medium ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
Cell Contact ◽  
T Helper ◽  
Th Cells ◽  
Inflammatory Microenvironment ◽  
Helper Cells

Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell−cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.

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