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Stadt Ulm, Deutschland

Spokesperson

Prof. Dr. Karin Scharffetter-Kochanek
Klinik für Dermatologie und Allergologie
Albert-Einstein-Allee 23
89081 Ulm


Head

Prof. Dr. Hartmut Geiger
Klinik für Dermatologie und Allergologie
Universität Ulm
James Franck-Ring 11c
89081 Ulm


Project 7

Regulation of murine CD8+ T-cell response with advanced age

Selective vaccination strategies can induce efficient CD8+ T-cell responses in aged mice (older than 2 years). Specific memory CD8+ T-cells were introduced into 3 month old mice and then activated 21 months later (when the mice are 2 years old). We observed a hyperactivated specific T-cell response, even though Foxp3+ CD4 regulatory T-cells (Treg) (which control the level of cellular immune response induction) are dramatically increased in aged mice. In contrast, although various vaccination protocols were attempted, we were unable to induce humoral immunity in aged mice.

In the second funding period, we will investigate from which CD8 T-cell compartment specific CD8 T-cell reactivation can be recruited by vaccination of aged mice. Less than 5% of peripheral CD8 T-cells are naive in aged mice, and the functional competence of these "aged" (oligoclonal and rapidly proliferating) naive T-cells is a controversial topic. The immunophenotypical profile (CD44, CD62L, CD127, CCR7, CD122, KLRG1, CD69, PD-1) of the dominant population of CD8 memory T-cells (TM) in spleen and bone marrow of aged mice is heterogeneous and differs from the corresponding TM cell population of younger mice. Using multiparameter FACS analyses (in cooperation with P8), we have identified polyclonal and specific (tetramer+) CD8 TM cell populations from spleen and bone marrow from aged (and young) mice, whose functional competence for adoptive transfer will be similarly evaluated.

If we can identify specific (or polyclonal) "aged" CD8 TM subpopulations whose adoptive value can be efficiently activated by vaccination, then we will analyze their sensitivity to regulatory control by young versus old Foxp3+ CD4 Treg. Using a model in which autoreactive CD8 T-cells induce “experimental autoimmune diabetes” (EAD), we have demonstrated that vaccination of aged mice generates preproinsulin, diabetes gene-specific CD8+ T-cells.

The CD8+ T-cell subpopulation, from which autoreactive pathogenic CD8+ T-cells will be generated in old age by immunization, will be verified using the strategy described above. The regulatory control of induction and/or effector phase diabetogenic CD8+ T-cells will be compared between young and old mice. The planned experiments focus on the question whether specific (anti-viral or autoreactive) CD8+ T-cell responses in old age is due to activation of naive CD8+ T-cells or cross-reactive CD8+ TM cells, which can probably be controlled by alternative Treg subsets/functions.

Chief Investigator

Prof. Dr. Reinhold Schirmbeck
University Medical Center
Center of Internal Medicine
Department of Internal Medicine I
Albert Einstein Allee 23
86381 Ulm
Germany

Phone: +49 (0)731 5004 4685
Fax.: +49 (0)731 5004 4502
reinhold.schirmbeck[at]uniklinik-ulm.de

References

List of publications from:
Reinhold Schirmbeck
>> Pubmed


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