Jan Herter - CAP 13

The overall aim of our group is investigating the reactivation of lymphocytes in non-lymphoid tissue: following lymphocyte priming, effector T cell recruit to peripheral tissues to fulfil both helper and executive functions. Our goal is to better understand the molecular mechanisms driving this process, to identify and characterize cellular interactions involved and to further understand microenvironmental cues modulating the functional restimulation of lymphocytes in peripheral tissue.

Introduction

Adaptive immunity is a crucial mediator of host defence. Following a developmental maturation of positive and negative selection in the thymus, naïve lymphocytes circulate through secondary lymphoid tissues. Upon encountering an antigen fitting to their unique antigen (T cell) receptor, a process of proliferation and differentiation follows (“priming”). At the end of this mostly subclinical process, a variety of effector T cells exits the lymph nodes and enters the blood stream. Once recruited to peri-pheral tissues, these cells may perform immune-suppressive or pro-inflammatory helper function or mediate direct effects on surrounding cells and tissue. It is at this stage that patients usually develop symptoms and are seen in the hospital. The functionality of these processes is a crucial deter-minant of the outcome of the disease. However, little is known about the mechanisms driving and modulating this crucial part of our immune response.

Cellular interactions driving reactivation

In contrast to CD8 T cells, CD4 cells require additional stimuli to fulfil their effector functions: recent publications have demonstrated that a functional response requires representation of the specific antigen by antigen presenting cells at the site of inflammation. However, little is known about this interaction that exhibits unique features that fundamentally differ from the priming process in lymph nodes. One focus of our lab is the characterization of cells mediating reactivation in tissues and environmental cues influencing this interaction. Interestingly, the transcriptional and epigenetic identity of antigen presenting cells differs significantly from organ to organ and existing evidence points to tissue specific variations of this process. We employ both in vivo (Figure 1) and in vitro assays (Figure 2) to assess the dynamics and quality of these interactions. Furthermore, we employ flow cytometry based approaches to investigate and probe cell-cell interactions.

Molecular mechanisms of reactivation

A growing body of literature points to unique features of the signalling pathways driving reactivation: past studies of our lab indicate that CD4 cells discriminately regulate their surface receptor display following serial contacts with antigen presenting cells (Figure 3).

This mechanism allows a form of signal integration in between cell-cell contacts by amplifying consecutive engagements via increase resurfacing of endocytosed receptor complexes. This process is dispensable for priming of naïve cells. We are interested in unique features of reactivating interactions to identify novel, specific therapeutic targets to modulate the tissue T cell response in favour of the patient. To achieve this aim we correlate our findings to patient samples (Figure 4).

Perspectives

An increasing body of evidence highlights the clinical potential of a previously unappreciated immunmodulatory feature of radiation therapy: radiation of peripheral tissues is capable of triggering adaptive immune responses, most likely via liberation of novel antigens and a modulation of the microenviroment. We aim to investigate the mechanisms driving these effects on the adaptive immune system.