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Review
, 39 (7), 515-23

The Role of Lymphatic Niches in T Cell Differentiation

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Review

The Role of Lymphatic Niches in T Cell Differentiation

Tara Capece et al. Mol Cells.

Abstract

Long-term immunity to many viral and bacterial pathogens requires CD8(+) memory T cell development, and the induction of long-lasting CD8(+) memory T cells from a naïve, undifferentiated state is a major goal of vaccine design. Formation of the memory CD8(+) T cell compartment is highly dependent on the early activation cues received by naïve CD8(+) T cells during primary infection. This review aims to highlight the cellularity of various niches within the lymph node and emphasize recent evidence suggesting that distinct types of T cell activation and differentiation occur within different immune contexts in lymphoid organs.

Keywords: CD8 T cell; T cell; chemokine; immune memory; lymph node.

Figures

Fig. 1.
Fig. 1.
Localization within the lymph node regulates differentiation. (A) CCR7+ naïve CD8+ T cells and Ag-bearing DCs localize in the paracortical region (Inner Cortex, blue) of the lymph node via stromal cell (blue lines) produced CCL21/CCL19 signals. Here, CD8+ T cells undergo three phases of activation characterized by their motility and DC interactions. Key signals guiding cell behavior and differentiation are highlighted. (B) After initial activation signals, T cells undergo cell division. Symmetric cell division (upper panel) accounts for a majority of cell division and yields daughter cells with similar surface and intracellular protein content. Current dogma indicates that signals received during early activation, such as initial T-DC signal duration and cytokine exposure, regulate cell differentiation. Additionally, later in the immune response, activated T cells may receive additional signals to drive differentiation towards memory phenotypes. A small subset of recently activated T cells undergoes cell division while in contact with a DC (lower panel), allowing intracellular polarity dictated by signaling at the T-APC contact site to be maintained throughout division. Daughter cells proximal to the DC inherit surface and intercellular proteins that give rise to effector cells, while distal daughter cells acquire a memory phenotype. (C, D) During the inflammatory response, the lymph node undergoes chemical and physical changes that give rise to specialized cellular niches with unique cytokine and chemokine profiles. Microniche composition is determined by existing stromal cells and cells residing in the macroniche. Expression of chemokine receptors and integrins on recently activated T cells guide entry to microniches, allowing cells to receive distinct cytokine and costimulatory signals (highlighted in each panel). For example, recently activated T cells reduce CCR7 and increase CXCR3, CXCR4, and CXCR5 expression to various degrees. Diverse expression levels allow T cells to respond to chemokines expressed in the outer cortex (purple), B cell follicles (pink), and SCS (yellow), providing access to distinct microniches. Activated CD8+ T cells localize through CXCL9/10/11 signals to the SCS, which contains macrophages, neutrophils, natural killer cells, and marginal reticular cells. Additionally CD4+ T cells and DCs migrate to the outer cortex, which is rich in B cells, FDCs, and chemokines CXCL12 and CXCL13. While simplified, the schematic highlights the complexity of lymphatic organization and microniches (C–D), which should not be viewed as discrete entities, but rather overlapping gradients and cues. (E) Surface expression levels arising from early activation signals and cell division guide effector and memory cells into distinct regions of the lymph node. Interactions within distinct microniches provide diverse costimulation and cytokine exposure, reinforcing or altering early differentiation programs.

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