scholarly journals Long-term humoral unresponsiveness in vivo, induced by treatment with monoclonal antibody against L3T4.

1986 ◽  
Vol 164 (3) ◽  
pp. 911-925 ◽  
Author(s):  
J Goronzy ◽  
C M Weyand ◽  
C G Fathman
Keyword(s):  
T Cell ◽  
Cell Subset ◽  
Cell Depletion ◽  
Helper Cell ◽  
Cell Subpopulation ◽  
Soluble Antigen ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Antibody Treatment

mAbs directed against the L3T4 molecule administered in vivo caused a severe and long lasting helper cell depletion in mice. Regeneration of the L3T4+ subpopulation occurred gradually (2-3 mo) after a single antibody treatment. Experiments were designed to examine the humoral immunocompetence of such anti-L3T4-treated animals during and after regeneration of the L3T4+ T cell subset. The animals were injected with anti-L3T4, immunized with soluble antigen, and challenged with antigen every 2 wk. Antibody responses to two antigens, sperm whale myoglobin (SpWMb) and KLH, which differ with regard to their immunogenicity, were compared. The lack of humoral immune responsiveness to either of these two antigens shorty after anti-L3T4 treatment responsiveness to either of these two antigens shortly after anti-L3T4 treatment was probably due to clonal depletion. The anti-L3T4-induced immunosuppressive effect on antibody production seemed to be determined in part by the preexisting T cell repertoire, as was suggested by the recovery of responsiveness to the highly immunogenic antigen KLH and the transient inhibitory effect of anti-L3T4 treatment in primed animals. The regenerating L3T4+ T cell subpopulation was relatively incompetent in initiating B cell responses. More than 40% of the L3T4+ T cell compartment had to recover to provide help for the production of anti-KLH antibodies, whereas elimination of 90% of the L3T4+ helper cells did not inhibit a primary anti-KLH response. Evidence for a heterogeneous composition of the L3T4+ subset came from experiments using rIL-2 in vivo. The addition of rIL-2 during early helper cell depletion improved the recovery of the humoral responsiveness without apparently affecting the kinetics of the regeneration of L3T4+ T cells. Interestingly, humoral unresponsiveness to the weakly immunogenic antigen SpWMb persisted for at least 120 d. This long lasting unresponsiveness could not be explained by clonal depletion, and suggested as one possibility that the presence of antigen during regeneration of the L3T4+ helper cell population may have influenced the ultimate T cell repertoire.

scholarly journals Chronic Soluble Antigen Sensitization Primes a Unique Memory/Effector T Cell Repertoire Associated with Th2 Phenotype Acquisition In Vivo

2002 ◽  
Vol 168 (1) ◽  
pp. 179-187 ◽  
Author(s):  
Gilles Foucras ◽  
Alexandra Gallard ◽  
Christiane Coureau ◽  
Jean-M. Kanellopoulos ◽  
Jean-Charles Guéry
Keyword(s):  
T Cell ◽  
Soluble Antigen ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Effector T Cell

Mls AND THE HELPER T-CELL REPERTOIRE I. Mls as a regulator of T-helper cell activation

1988 ◽  
Vol 15 (1-3) ◽  
pp. 169-174 ◽  
Author(s):  
U. Hämmerling ◽  
M. Toulon ◽  
R. G. E. Palfree ◽  
M. K. Hoffmann
Keyword(s):  
T Cell ◽  
Cell Activation ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Cell Repertoire ◽  
T Helper ◽  
Helper T Cell ◽  
Cell Repertoire

Abstract 5017: T-cell repertoire turnover induced by anti-CTLA-4 antibody treatment in cancer patients

2014 ◽  
Author(s):  
Lawrence H. Fong ◽  
Edward Cha ◽  
Mark Klinger ◽  
Yafei Hou ◽  
Craig Cummings ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Patients ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Antibody Treatment

Effect of anti-CTLA-4 antibody treatment on T-cell repertoire evolution in treated cancer patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3020-3020
Author(s):  
Edward Cha ◽  
Yafei Hou ◽  
Mark Klinger ◽  
Craig Cummings ◽  
Malek Faham ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Multiple Time ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Antibody Treatment ◽  
Tcr Repertoire ◽  
Tcr Diversity ◽  
Morisita Index

3020 Background: CTL-associated antigen 4 (CTLA-4) is an immune checkpoint expressed by T cells. While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, its effects on the breadth of the T cell response is unknown. Methods: We used a sequencing-based method, LymphoSIGHT, to assess T cell repertoire diversity in 46 patients with metastatic castration resistant prostate cancer or metastatic melanoma. Peripheral blood mononuclear cells were obtained from patients prior to and during treatment with anti-CTLA-4 antibody. mRNA was amplified using locus-specific primer sets for T cell receptor (TCR) beta, and the amplified product was sequenced. Sequence reads were used to quantitate absolute TCR frequencies using standardized clonotype determination algorithms with normalization by spiked reference TCR sequences. Following clonotype quantitation, repertoire differences between serial samples were assessed by the Morisita index, a statistical measure of population dispersion. Results: 97 paired samples were assessed, of which 46 (47%) had increases and 22 (23%) had decreases in TCR diversity by more than 2-fold. By comparison, none of 9 untreated sample pairs underwent more than a 2-fold change in diversity (P = 0.005, Fisher’s exact test, two tailed). TCR repertoire differences between monthly samples were markedly higher than for time-matched controls. After the first treatment, median Morisita index between samples was 0.197 for treated samples versus 0.039 for untreated (P = 0.0005, Mann-Whitney U test). The median number of clones that significantly changed in abundance was 421 for treated versus 45 for controls. In patients with multiple time points, this rapid clonotype evolution continued through treatment. Despite this global turnover in repertoire, a subset of high frequency clones, including CMV-specific T cells, remained relatively constant over the course of the study. Conclusions: CTLA-4 blockade increases the global rate of T cell clonotype turnover and influences TCR diversity. This evolution of the TCR repertoire may reflect a mechanism by which CTLA-4 blockade enhances tumor-specific T cells over time.

scholarly journals In vivo positive selection determines the peptide and MHC specificity of the CD8 T cell repertoire

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Baomei Wang ◽  
Lonnie Lybarger ◽  
Tina Primeau ◽  
Ted H. Hansen ◽  
Janet M. Connolly
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
Cd8 T Cell ◽  
T Cell Repertoire ◽  
Cell Repertoire

scholarly journals Competitive Inhibition In Vivo and Skewing of the T Cell Repertoire of Antigen-Specific CTL Priming by an Anti-Peptide-MHC Monoclonal Antibody

2001 ◽  
Vol 167 (2) ◽  
pp. 699-707 ◽  
Author(s):  
Doo Hyun Chung ◽  
Igor M. Belyakov ◽  
Michael A. Derby ◽  
Jian Wang ◽  
Lisa F. Boyd ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Competitive Inhibition ◽  
T Cell Repertoire ◽  
Cell Repertoire

scholarly journals Mls-1-like superantigen in the MA/MyJ mouse is encoded by a new mammary tumor provirus that is distinct from Mtv-7.

1992 ◽  
Vol 175 (6) ◽  
pp. 1613-1621 ◽  
Author(s):  
C K Rudy ◽  
E Kraus ◽  
E Palmer ◽  
B T Huber
Keyword(s):  
T Cell ◽  
Mammary Tumor ◽  
Inbred Strains ◽  
Cell Receptor ◽  
Predicted Amino Acid Sequence ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Stimulation Of

Mls-1 is an endogenous superantigen that leads to in vivo deletion and in vitro stimulation of T cell receptor (TCR) V beta 6-, 7-, 8.1-, and 9-expressing cells. The MA/MyJ mouse deletes the identical set of TCR from its mature T cell repertoire; however, it does not contain Mtv-7, the murine mammary tumor provirus (MMTV), whose sag gene encodes Mls-1. Interestingly, the superantigen activity of this mouse strain segregates with a new mammary tumor provirus, Mtv-43, not seen in other inbred strains. The predicted amino acid sequence of the sag gene of Mtv-43 was compared with that of Mtv-7. Strikingly, the COOH terminus of the two molecules is very similar, while all other MMTV-encoded superantigens differ 100% in this segment.

scholarly journals Negative Selection during the Peripheral Immune Response to Antigen

2000 ◽  
Vol 193 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Stephen M. Anderton ◽  
Caius G. Radu ◽  
Pauline A. Lowrey ◽  
E. Sally Ward ◽  
David C. Wraith
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clonal Expansion ◽  
Cell Interaction ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Vitro Assay ◽  
High Affinity

Thymic selection depends on positive and negative selective mechanisms based on the avidity of T cell interaction with antigen–major histocompatibility complex complexes. However, peripheral mechanisms for the recruitment and clonal expansion of the responding T cell repertoire remain obscure. Here we provide evidence for an avidity-based model of peripheral T cell clonal expansion in response to antigenic challenge. We have used the encephalitogenic, H-2 Au-restricted, acetylated NH2-terminal nonameric peptide (Ac1-9) epitope from myelin basic protein as our model antigen. Peptide analogues were generated that varied in antigenic strength (as assessed by in vitro assay) based on differences in their binding affinity for Au. In vivo, these analogues elicited distinct repertoires of T cells that displayed marked differences in antigen sensitivity. Immunization with the weakest (wild-type) antigen expanded the high affinity T cells required to induce encephalomyelitis. In contrast, immunization with strongly antigenic analogues led to the elimination of T cells bearing high affinity T cell receptors by apoptosis, thereby preventing disease development. Moreover, the T cell repertoire was consistently tuned to respond to the immunizing antigen with the same activation threshold. This tuning mechanism provides a peripheral control against the expansion of autoreactive T cells and has implications for immunotherapy and vaccine design.

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