Biomedical subjects

Silke Schnell

Publications and source records attributed to Silke Schnell.

3 recordsLinked to original sources

PubMed2006

Constitutive expression of the pre-TCR enables development of mature T cells.

Expression and signalling through the pre-TCR and the TCRalphabeta resemble two critical checkpoints during T cell development. We investigated to which extent a pre-TCR can functionally replace mature TCRalpha chains during T cell development. For this purpose, transgenic mice were generated expressing the pre-TCRalpha (pTalpha) under the transcriptional control of TCRbeta regulatory elements. We report here on the interesting finding that constitutive pTalpha expression allows complete T cell maturation. The pre-TCR complex permits a subset of beta-selected thymocytes to mature in the absence of TCRalpha into peripheral T cells (betaT cells) comprising up to 10% of all lymphocytes. Lymphopenia-driven proliferation of these betaT cells is similar to that of conventional alphabetaT cells. Furthermore, betaT cells proliferated and acquired effector function upon stimulation with allogeneic MHC.

Animals↗

PubMed2006

Gimap4 accelerates T-cell death.

Gimap4, a member of the newly identified GTPase of the immunity-associated protein family (Gimap), is strongly induced by the pre-T-cell receptor in precursor T lymphocytes, transiently shut off in double-positive thymocytes, and reappears after TCR-mediated positive selection. Here, we show that Gimap4 remains expressed constitutively in the cytosol of mature T cells. A C-terminal IQ domain binds calmodulin in the absence of calcium, and conserved PKC phosphorylation motifs are targets of concanavalin A (ConA)- or PMA/ionomycin-induced PKC activation. To address the role of Gimap4 in T-cell physiology, we completed the genomic organization of the gimap4 locus and generated a Gimap4-null mutant mouse. Studies in these mice revealed no critical role of Gimap4 in T-cell development but in the regulation of apoptosis. We have found that Gimap4 accelerates the execution of programmed cell death induced by intrinsic stimuli downstream of caspase-3 activation and phosphatidylserine exposure. Apoptosis directly correlates with the phosphorylation status of Gimap4.

Animals↗

PubMed2003

Visualizing the course of antigen-specific CD8 and CD4 T cell responses to a growing tumor.

Spontaneous tumors frequently express antigens that can be recognized by the immune system but nevertheless manage to evade immune surveillance. To better understand the mechanism of evasion, we followed CD8 and CD4 T cells reacting against a subcutaneously growing tumor, modified to express influenza hemagglutinin (HA) as surrogate tumor antigen. Adoptive transfer of 8,000 antigen-specific CD8 T cells was sufficient to protect against challenge with 1x10(6) tumor cells, while larger numbers of T cells rejected established tumors. HA-specific CD4 T cells could not reject tumors on their own but helped rejection by CD8 T cells. Rejection of the tumor coincided with prolonged survival of expanded antigen-specific CD8 and CD4 T cells, while a failing anti-tumor response was accompanied by transient expansion followed by rapid elimination of antigen-specific T cells. Thus, a highly immunogenic tumor can evade immune surveillance because of an insufficient number of tumor-specific T cells and antigen overload, resulting in exhaustion of the immune response. In this scenario, adoptive immunotherapy rather than vaccination promises successful treatment.

Animals↗