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DNA sequence analysis of T-cell receptor genes reveals an oligoclonal T-cell response to a tumor with multiple target
S Seung1, J L Urban, H Schreiber
1Department of Pathology, University of Chicago, Illinois 60637.
Abstract:
Human and murine cancers can express multiple independent antigens as targets for cytolytic T-cells (CTLs). The immune response against one such tumor was studied at the cellular and molecular level by analyzing the T-cell receptor beta chains of CTLs responding in vivo to a murine UV light-induced cancer. A 5-13-fold enhancement of V beta 13+ CTLs above background (naive spleen, 4-5% V beta 13+ among CD8+ T-cells) was demonstrated in the responses of ten individual animals to this tumor. The dominance of V beta 13 usage was exclusively limited to the CD8+ compartment and correlated with recognition of the A but not the B and C antigens on the tumor. In addition, the amino acid sequences of the putative third complementarity determining regions of the T-cell receptor beta chains of CTLs isolated in vivo were remarkably similar to each other suggesting restriction also at the clonal level. Cells responding to four other syngeneic UV-induced tumors, each expressing different unique antigens, or to a variant of the same tumor that had selectively lost the A but retained the independent B and C antigens, induced a 2-fold or less enhancement of V beta 13+ CD8+ cells above background. Thus, the host responds to only one of the several possible target antigens and with relatively few CTL clonotypes.
Insights
The immune system targets specific antigens on tumors using cytolytic T-cells (CTLs). This study reveals that the host immune response focuses on a single tumor antigen, utilizing a limited repertoire of CTL clonotypes.
Area of Science:
- Immunology
- Cancer Research
- T-cell Biology
Background:
- Cancers can present multiple antigens to the immune system.
- Cytolytic T-cells (CTLs) are crucial for tumor surveillance.
- Understanding T-cell receptor (TCR) usage provides insights into immune responses.
Purpose of the Study:
- To investigate the cellular and molecular basis of CTL responses to a murine UV-induced cancer.
- To analyze the T-cell receptor beta chain usage of responding CTLs.
- To determine antigen specificity and clonotypic restriction of the anti-tumor immune response.
Main Methods:
- Analysis of T-cell receptor beta chain usage in CTLs from tumor-bearing mice.
- Flow cytometry to quantify V beta 13+ CTLs within the CD8+ T-cell compartment.
- Assessment of immune response to tumors with varying antigen expression profiles.
Main Results:
- A significant expansion (5-13 fold) of V beta 13+ CTLs was observed in response to a specific tumor.
- This V beta 13 usage was restricted to the CD8+ T-cell subset and correlated with recognition of tumor antigen A.
- Responses to tumors lacking antigen A or expressing different antigens showed minimal V beta 13+ CTL expansion.
- Sequencing of TCR beta chains revealed remarkable similarity, indicating clonal restriction.
Conclusions:
- The host immune system preferentially targets a single tumor antigen.
- The anti-tumor CTL response is characterized by a restricted usage of V beta 13 and limited clonotypes.
- This suggests a focused immune response rather than a polyclonal attack against multiple tumor antigens.