Innate control of adaptive immunity via remodeling of lymph node feed arteriole

We have used a TCR-transgenic CD8+ T cell adoptive transfer model to examine the tempo of T cell activation and proliferation in the draining lymph nodes (DLN) in response to respiratory virus infection. The T cell response in the DLN differed for mice infected with different type A influenza strains with the onset of T cell activation/proliferation to the A/JAPAN virus infection preceding the A/PR8 response by 12–24 h. This difference in T cell activation/proliferation correlated with the tempo of accelerated respiratory DC (RDC) migration from the infected lungs to the DLN in response to influenza virus infection, with the migrant RDC responding to the A/JAPAN infection exhibiting a more rapid accumulation in the lymph nodes (i.e., peak migration for A/JAPAN at 18 h, A/PR8 at 24–36 h). Furthermore, in vivo administration of blocking anti-CD62L Ab at various time points before/after infection revealed that the virus-specific CD8+ T cells entered the DLN and activated in a sequential “conveyor belt”-like fashion. These results indicate that the tempo of CD8+ T cell activation/proliferation after viral infection is dependent on the tempo of RDC migration to the DLN and that T cell activation occurs in an ordered sequential fashion.

Section: Discussionmentioning

confidence: 90%

Sequential Activation of CD8+ T Cells in the Draining Lymph Nodes in Response to Pulmonary Virus Infection

Yoon

Legge

Sung

et al. 2007

“…In the steady state, as much as 50% of recirculating lymphocytes passing through an LN exit through the efferent lymph (5). During inflammation, LN activation triggers remodeling of high endothelial venules (HEVs) to increase lymphocyte entry by manyfold (11,12). Undesirable situations, including LN hypertrophy and hyperactivation, which are often associated with autoimmune and chronic inflammatory diseases, may arise if these lymphocytes fail to leave the inflamed LNs in a timely manner.…”

Section: Discussionmentioning

confidence: 99%

“…However, recent studies indicated that plasticity in LN structural organization continues to exist throughout life, particularly during inflammation and infection (8,9). Reorganization of LN microanatomy during inflammation is characterized by the remodeling and expansion of key LN stromal cells, including lymphatic endothelial cells (LECs) (10), blood endothelial cells (BECs) (11,12), and fibroblastic reticular cells (FRCs) (13,14). Importantly, increasing evidence reveal the immunological significance of the remodeling of these stromal elements.…”

mentioning

confidence: 99%

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Expansion of Cortical and Medullary Sinuses Restrains Lymph Node Hypertrophy during Prolonged Inflammation

Tan

Yeo

Wong

et al. 2012

During inflammation, accumulation of immune cells in activated lymph nodes (LNs), coupled with a transient shutdown in lymphocyte exit, results in dramatic cellular expansion. Counter-regulatory measures to restrain LN expansion must exist and may include re-establishment of lymphocyte egress to steady-state levels. Indeed, we show in a murine model that egress of lymphocytes from LNs was returned to steady-state levels during prolonged inflammation following initial retention. This restoration in lymphocyte egress was supported by a preferential expansion of cortical and medullary sinuses during late inflammation. Cortical and medullary sinus remodeling during late inflammation was dependent on temporal and spatial changes in vascular endothelial growth factor-A distribution. Specifically, its expression was restricted to the subcapsular space of the LN during early inflammation, whereas its expression was concentrated in the paracortical and medullary regions of the LN at later stages. We next showed that this process was mostly driven by the synergistic cross-talk between fibroblastic reticular cells and interstitial flow. Our data shed new light on the biological significance of LN lymphangiogenesis during prolonged inflammation and further underscore the collaborative roles of stromal cells, immune cells, and interstitial flow in modulating LN plasticity and function.

“…11) in part by inducing APC maturation and recruitment to lymphoid organs via the afferent lymphatics (12,13). Furthermore, recent reports showed that inflammation induced by a TLR4 or TLR9 agonist controlled naive lymphocyte recirculation in an Agindependent manner, resulting in an increase in the number of naive lymphocytes in the draining lymph node and an increase in the efficiency of lymphocyte-APC encounters (14). TLR-dependent lymph node hypertrophy was proposed to require vascular growth and arteriole thickening.…”

mentioning

confidence: 99%

CD73-Generated Adenosine Restricts Lymphocyte Migration into Draining Lymph Nodes

Takedachi

Qu²,

Ebisuno

et al. 2008

After an inflammatory stimulus, lymphocyte migration into draining lymph nodes increases dramatically to facilitate the encounter of naive T cells with Ag-loaded dendritic cells. In this study, we show that CD73 (ecto-5′-nucleotidase) plays an important role in regulating this process. CD73 produces adenosine from AMP and is expressed on high endothelial venules (HEV) and subsets of lymphocytes. Cd73−/− mice have normal sized lymphoid organs in the steady state, but ∼1.5-fold larger draining lymph nodes and 2.5-fold increased rates of L-selectin-dependent lymphocyte migration from the blood through HEV compared with wild-type mice 24 h after LPS administration. Migration rates of cd73+/+ and cd73−/− lymphocytes into lymph nodes of wild-type mice are equal, suggesting that it is CD73 on HEV that regulates lymphocyte migration into draining lymph nodes. The A2B receptor is a likely target of CD73-generated adenosine, because it is the only adenosine receptor expressed on the HEV-like cell line KOP2.16 and it is up-regulated by TNF-α. Furthermore, increased lymphocyte migration into draining lymph nodes of cd73−/− mice is largely normalized by pretreatment with the selective A2B receptor agonist BAY 60-6583. Adenosine receptor signaling to restrict lymphocyte migration across HEV may be an important mechanism to control the magnitude of an inflammatory response.