scholarly journals T-T cell interactions during in vitro cytotoxic T lymphocyte responses. V. Precursor frequencies and specificity of alloreactive helper T cells.

1982 ◽  
Vol 156 (1) ◽  
pp. 41-54 ◽  
Author(s):  
M Krönke ◽  
P Scheurich ◽  
K Pfizenmaier ◽  
M Röllinghoff ◽  
H Wagner
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Third Party ◽  
Antigen Specificity ◽  
Murine Spleen ◽  
Helper Activity ◽  
Ctl Responses

We assessed the quantitative representation and specificity of alloreactive helper T lymphocytes (HTL) within murine spleen cells by three different limiting dilution systems. For the induction of primary cytolytic T lymphocyte (CTL) responses towards alloantigens, a Lyt-1+23- HTL precursor (HTLp) could be defined, which occurred at frequencies of 1/2.000-1/50,000, depending on the alloantigen in question. The HTLp limiting for interleukin-2 (Il-2) production also expressed the Lyt-1+ phenotype and occurred in similar frequencies. This cell type was concluded to be the limiting HTLp for the overall helper activity required for the induction of primary CTL responses. HTLp reactive to Mlsa -encoded antigens occurred at higher frequencies (1/500) than those reactive towards whole allogeneic H-2 haplotypes (1/4,000-1/7,000). Within the H-2 complex, I region-encoded alloantigens activated approximately 10 times more HTLp than did H-2K or H-2D regions. When alloreactive HTL were tested for antigen specificity at the clonal level, approximately 80% of the HTL clones proved to be specific to the alloantigen used for immunization, whereas approximately 20% reacted also towards third-party alloantigens. The data are discussed with respect to putative T-T interactions within the helper T cell population and the precision of alloantigen recognition by HTL.

scholarly journals Cytotoxic T lymphocyte responses by chimeric thymocytes. Self-recognition is determined early in T cell development.

1981 ◽  
Vol 153 (1) ◽  
pp. 13-29 ◽  
Author(s):  
A M Kruisbeek ◽  
R J Hodes ◽  
A Singer
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Third Party ◽  
Receptor Repertoire ◽  
Histocompatibility Complex ◽  
Self Recognition ◽  
Lymphocyte Responses ◽  
Bone Marrow Chimeras

In this study the cytotoxic T lymphocyte (CTL) recognition pattern of thymocytes from recently reconstituted parent leads to F1 and F1 leads to parent radiation bone marrow chimeras was investigated. Chimeric thymocytes were entirely of donor origin approximately 4 wk after irradiation and reconstitution but were not capable of autonomously generating either alloreactive or trinitrophenyl (TNP)-modified-self-reactive CTL responses. However, in the presence of interleukin-2 (I1-2), the the putative T helper cell product, CTL could be generated in vitro by thymocytes from recently reconstituted chimeras. Experiments with thymocytes from A leads to A X B and A X B leads to A chimeras revealed the following: (a) thymocytes from both types of chimeras were nonreactive to either A or B parental major-histocompatibility complex (MHC) determinants even though they were alloreactive to third-party stimulator cells; and (b) thymocytes from these chimeras were restricted to the recognition of TNP in association with MHC determinants syngeneic to the chimeric host. Thus, these experiments demonstrate that even at the earliest time CTL effectors of donor origin from the thymuses of chimeras can be studied, their self-receptor repertoire has already been restricted to recognition of host MHC determinants. These results support the concept that the host environment influences the self-recognition capacity of T cells at the pre- or intrathymic stage of differentiation.

Anti–third-party veto CTLs overcome rejection of hematopoietic allografts: synergism with rapamycin and BM cell dose

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 1943-1950 ◽  
Author(s):  
Esther Bachar-Lustig ◽  
Shlomit Reich-Zeliger ◽  
Yair Reisner
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Allogeneic Transplantation ◽  
Third Party ◽  
Major Histocompatibility Antigens ◽  
Veto Cells

Abstract Several bone marrow cells and lymphocyte subpopulations, known as “veto cells,” were shown to induce transplantation tolerance across major histocompatibility antigens. Some of the most potent veto cells are of T-cell origin, and in particular a very strong veto activity was documented for cytotoxic T-lymphocyte (CTL) lines or clones. However, these cells also possess marked graft-versus-host (GVH) reactivity. In the present study we evaluated a new approach to deplete CTLs of antihost clones by stimulating the donor T cells against third-party stimulators in the absence of exogenous interleukin 2 (IL-2). We demonstrate that such CTLs are depleted of GVH reactivity while maintaining marked veto activity in vitro. Furthermore, marked synergism was exhibited between the veto CTLs and rapamycin when tested in a murine model, which measures T-cell–mediated bone marrow allograft rejection, or in sublethally irradiated allogeneic hosts. Our results suggest that engraftment of early progenitors could be enhanced by using host-nonreactive anti–third-party CTLs, in conjunction with nonmyeloablative rapamycin-based conditioning protocols, thereby significantly reducing the toxicity of allogeneic transplantation.

scholarly journals Sendai virus-specific, H-2-restricted cytotoxic T lymphocyte responses of nude mice grafted with allogeneic or semi-allogeneic thymus glands.

1980 ◽  
Vol 152 (6) ◽  
pp. 1805-1810 ◽  
Author(s):  
J P Lake ◽  
M E Andrew ◽  
C W Pierce ◽  
T J Braciale
Keyword(s):  
T Lymphocyte ◽  
Nude Mice ◽  
Sendai Virus ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Self Recognition ◽  
Parental Haplotype ◽  
Lymphocyte Responses ◽  
Ctl Responses

The in vitro secondary cytotoxic T lymphocyte (CTL) response to Sendai virus-treated stimulator cells by primed spleen cells from thymus gland-grafted nude mice was examined. BALB/c (H-2d) nude mice grafted with allogeneic C57BL/10 (H-2b) thymus glands developed CTL responses directed exclusively to Sendai virus-infected H-2d target cells. (C57BL/6 X BALB/c)F1 nude mice grafted with thymus glands of either parent developed CTL responses preferentially against infected target cells expressing the MHC antigens present in the parental thymus graft, but also had detectable activity for infected target cells of the parental haplotype not expressed in the thymus. These results provide evidence against the concept that self recognition by MHC-restricted CTL is directed exclusively by the MCH type of the thymus.

scholarly journals Enhanced immune activity of cytotoxic T-lymphocyte epitope analogs derived from positional scanning synthetic combinatorial libraries

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1776-1786 ◽  
Author(s):  
Corinna La Rosa ◽  
Radhika Krishnan ◽  
Susan Markel ◽  
Jonathan P. Schneck ◽  
Richard Houghten ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Combinatorial Libraries ◽  
Peptide Sequence ◽  
Ctl Epitopes ◽  
Ctl Epitope ◽  
Positional Scanning ◽  
Synthetic Combinatorial Libraries

The pp65495-503 cytotoxic T-lymphocyte (CTL) epitope from cytomegalovirus (CMV) is universally recognized among CMV+ individuals who express an allele of the human leukocyte antigen A (HLA-A*0201). The relative binding affinity of the epitope to HLA-A*0201 is moderate, and its increased activity might prove beneficial in its use as a CTL epitope vaccine. A new approach to enhance the activity of T-cell epitopes is the use of positional scanning synthetic combinatorial libraries (PS-SCLs). Using a nonamer PS-SCL, the pp65495-503 epitope was modified after screening a CMV-specific T-cell clone (TCC) (3-3F4) from which the native peptide sequence was derived. Two peptides with amino acid substitutions at P1, P3, P7, and P8 are between 103 and 104 more active than the native epitope. Although the native CTL epitope terminates as a free acid, both tetrasubstituted peptides only function as CTL epitopes when the carboxyl terminus is amidated. Selective substitution of the native sequence based on PS-SCL screening results identified 3 amidated monosubstituted and disubstituted peptides that are better recognized than the native epitope by TCCs from a cohort expressing HLA-A*0201. In vitro stimulation of peripheral blood mononuclear cells with each of the peptide epitope analogs stimulated memory CTLs, which recognized CMV-infected targets among a high percentage of CMV+ individuals. Binding studies of peptide analogs with HLA-Ig (immunoglobulin) dimers and 2 different TCCs correlated with in vitro lysis results. These data suggest that increasing the activity of CTL epitopes while maintaining broad recognition is possible, which holds promise for vaccine development in infectious disease and cancer.

scholarly journals Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by the Salmonella Type III Secretion Antigen Delivery System

2003 ◽  
Vol 77 (4) ◽  
pp. 2400-2409 ◽  
Author(s):  
David T. Evans ◽  
Li-Mei Chen ◽  
Jacqueline Gillis ◽  
Kuei-Chin Lin ◽  
Brian Harty ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Replication ◽  
T Lymphocyte ◽  
Type Iii Secretion ◽  
Cytotoxic T Lymphocyte ◽  
Rhesus Macaques ◽  
Secretion System ◽  
Type Iii ◽  
Immunodeficiency Virus ◽  
Ctl Responses

ABSTRACT Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested ΔphoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01 + macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag181-189 epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag181-189-specific CD8+ T-cell responses in peripheral blood. A significant percentage of the Gag181-189-specific T-cell population in each animal also expressed the intestinal homing receptor α4β7. Additionally, Gag181-189-specific CD8+ T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model.

Generation of cytotoxic immune responses during the progression of a rat glioma

1994 ◽  
Vol 80 (1) ◽  
pp. 90-96 ◽  
Author(s):  
Frank P. Holladay ◽  
Rajani Choudhuri ◽  
Teresa Heitz ◽  
Gary W. Wood
Keyword(s):  
Immune Responses ◽  
Tumor Progression ◽  
Tumor Cells ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Autologous Tumor ◽  
Content Type ◽  
Tumor Associated Antigens

✓ Cytotoxic T lymphocytes specific for tumor-associated antigens are produced by exposing animals to tumor cells and stimulating lymphocytes from animals immunized in vitro with tumor cells and small amounts of interleukin-2 (IL-2). This study was designed to determine whether a fast-growing immunogenic avian sarcoma virus-induced glioma produces primed cytotoxic T lymphocyte precursors during its progression. Lymphocytes from intracerebral glioma-bearing rats generally failed to proliferate in vitro in response to immunization with tumor cells and IL-2 and, when proliferative responses were observed, the lymphocytes were not cytotoxic for glioma cells. However, when the same tumor was growing subcutaneously, lymphocytes proliferated and exhibited glioma-specific cytotoxicity when stimulated in vitro with autologous tumor cells and IL-2. Subcutaneous immunization of intracerebral glioma-bearing rats with tumor cells and adjuvant induced strong cytotoxic T lymphocyte responses. The results demonstrated that, while intracerebral tumor progression itself does not induce an antiglioma immune response, immune responses to tumor-associated antigens may be induced by systemic immunization of tumor-bearing animals. The results suggest that the immunogenicity of brain tumors is masked by the immunologically privileged status of the brain, not by the induction of generalized immune suppression during tumor progression.

Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion

Blood ◽  
2006 ◽  
Vol 108 (13) ◽  
pp. 4260-4267 ◽  
Author(s):  
Petra Hoffmann ◽  
Ruediger Eder ◽  
Tina J. Boeld ◽  
Kristina Doser ◽  
Biserka Piseshka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Lines ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Solid Organ ◽  
Cell Therapies ◽  
In Vitro Expansion

Abstract Thymus-derived CD4+CD25+ regulatory T cells suppress autoreactive CD4+ and CD8+ T cells and thereby protect from autoimmunity. In animal models, adoptive transfer of CD4+CD25+ regulatory T cells has been shown to prevent and even cure autoimmune diseases as well as pathogenic alloresponses after solid organ and stem-cell transplantations. We recently described methods for the efficient in vitro expansion of human regulatory T cells for clinical applications. We now demonstrate that only CCR7- and L-selectin (CD62L)–coexpressing cells within expanded CD4+CD25high T cells maintain phenotypic and functional characteristics of regulatory T cells. Further analysis revealed that these cells originate from CD45RA+ naive cells within the CD4+CD25high T-cell compartment, as only this subpopulation homogeneously expressed CD62L, CCR7, cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), and forkhead box P3 (FOXP3), produced no inflammatory cytokines and maintained robust suppressive activity after expansion. In contrast, cell lines derived from CD45RA– memory-type CD4+CD25high T cells lost expression of lymph node homing receptors CCR7 and CD62L, contained interleukin-2 (IL-2) and interferon-γ (IFN-γ) as well as IL-10–secreting cells, showed only moderate suppression and, most importantly, did not maintain FOXP3 expression. Based on these unexpected findings, we suggest that isolation and expansion of CD45RA+ naive CD4+ CD25high T cells is the best strategy for adoptive regulatory T (Treg)–cell therapies.

scholarly journals Acute Resolving Woodchuck Hepatitis Virus (WHV) Infection Is Associated with a Strong Cytotoxic T-Lymphocyte Response to a Single WHV Core Peptide

2007 ◽  
Vol 81 (13) ◽  
pp. 7156-7163 ◽  
Author(s):  
Ina Frank ◽  
Claudia Budde ◽  
Melanie Fiedler ◽  
Uta Dahmen ◽  
Sergei Viazov ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Cell Response ◽  
Cytotoxic T Lymphocyte ◽  
Hepatitis Virus ◽  
Immunological Response ◽  
T Cell Response ◽  
Woodchuck Hepatitis Virus ◽  
Core Peptide ◽  
Ctl Responses

ABSTRACT Woodchucks infected with woodchuck hepatitis virus (WHV) are an excellent model for studying acute, self-limited and chronic hepadnaviral infections. Defects in the immunological response leading to chronicity are still unknown. Specific T-helper cell responses to WHV core and surface antigens (WHcAg and WHsAg, respectively) are associated with acute resolving infection; however, they are undetectable in chronic infection. Up to now, cytotoxic T-lymphocyte (CTL) responses could not be determined in the woodchuck. In the present study, we detected virus-specific CTL responses by a CD107a degranulation assay. The splenocytes of woodchucks in the postacute phase of WHV infection (18 months postinfection) were isolated and stimulated with overlapping peptides covering the whole WHcAg. After 6 days, the cells were restimulated and stained for CD3 and CD107a. One peptide (c96-110) turned out to be accountable for T-cell expansion and CD107a staining. Later, we applied the optimized degranulation assay to study the kinetics of the T-cell response in acute WHV infection. We found a vigorous T-cell response against peptide c96-110 with peripheral blood cells beginning at the peak of viral load (week 5) and lasting up to 15 weeks postinfection. In contrast, there was no T-cell response against peptide c96-110 detectable in chronically WHV-infected animals. Thus, with this newly established flow cytometric degranulation assay, we detected for the first time virus-specific CTLs and determined one immunodominant epitope of WHcAg in the woodchuck.

Sign in / Sign up

Export Citation Format

Share Document