Recognition of cognate MHC class II:peptide complexes by CD4+ T cells triggers large-scale molecular
rearrangements at the T- antigen presenting cells (APC) interface forming a structure called the immune
synapse. At the synapse, T cells capture large membrane fragments and associated proteins from the APC in
a process termed trogocytosis. While this phenomenon has the potential to significantly alter the biology of the
individual T cell, we currently have only a limited understanding of the biological consequences of this process.
We have previously shown that these molecules mediate intracellular signaling within the T cell, presumably by
engaging their receptors on the cell. We have recently discovered that trogocytosis-mediated signaling alters
gene expression in the cells. The trogocytosis positive cells express the chemokine receptor CXCR5, the BCL-
6 transcription factor, and secrete effector cytokines IL-21 and IL-4. This phenotype is consistent with the
follicular T helper cell (TFH) effector subset, suggesting that trogocytosis-mediated signaling may play a role in
TFH differentiation. TFH cells are critically important in control of antibody-mediated immune responses. They
respond to chemokine gradients and migrate into B cell follicles in secondary lymphoid organs where they
further differentiate and control the germinal center (GC) reaction. In the GC they interact with B cells to drive
antibody secretion, class switch recombination, and mediate somatic hypermutation. The current TFH
differentiation model involves initial T cell activation by dendritic cells (DC), which induces pre-TFH skewing.
Under antigen-limited conditions the T-DC interaction is followed by antigen presentation by B cells leading to
GC-TFH differentiation. However, if antigen is not limiting, TFH differentiation doesn't require B cells. It has been
suggested that the role of B cells in GC-TFH differentiation is sustained antigen presentation. This leads to an
important question: If the main role of B cells in TFH differentiation is to provide Ag for continual stimulation,
could trogocytosis-mediated signaling circumnavigate this necessity for B cells? In this proposal we will
examine whether trogocytosis-mediated signaling promotes TFH differentiation. In addition, we will assess the
contribution of trogocytosis by CD4+ T cells on humoral responses in vivo. Our hypothesis is that
trogocytosis contributes to humoral responses by sustaining TFH effector cytokine production and
contributing to the differentiation of TFH cells. We will address this hypothesis with 2 specific aims: #1:
Trogocytosis-mediated signaling promotes TFH differentiation in the absence of APC; #2. Trogocytosis-
mediated signaling will lead to more efficient and/or rapid) accumulation of trog+ cells to the B cell follicles
and/or germinal centers, where they interact with B cells to drive Ig secretion and class switch recombination.
The results from these experiments will provide important insights into TFH differentiation and the role of
trogocytosis in the generation and maintenance of humoral immune responses. These studies will lead
ultimately to additional lines of inquiry related to the functions of trogocytosis in immune pathologies.
