Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues.

It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life.

Airway CD8(+) T Cells Are Associated with Lung Injury during Infant Viral Respiratory Tract Infection.

Infants and young children are disproportionately susceptible to severe complications from respiratory viruses, although the underlying mechanisms remain unknown. Recent studies show that the T cell response in the lung is important for protective responses to respiratory infections, although details on the infant/pediatric respiratory immune response remain sparse. The objectives of the present study were to characterize the local versus systemic immune response in infants and young children with respiratory failure from viral respiratory tract infections and its association to disease severity. Daily airway secretions were sampled from infants and children 4 years of age and younger receiving mechanical ventilation owing to respiratory failure from viral infection or noninfectious causes. Samples were examined for immune cell composition and markers of T cell activation. These parameters were then correlated with clinical disease severity. Innate immune cells and total CD3(+) T cells were present in similar proportions in airway aspirates derived from infected and uninfected groups; however, the CD8:CD4 T cell ratio was markedly increased in the airways of patients with viral infection compared with uninfected patients, and specifically in infected infants with acute lung injury. T cells in the airways were phenotypically and functionally distinct from those in blood with activated/memory phenotypes and increased cytotoxic capacity. We identified a significant increase in airway cytotoxic CD8(+) T cells in infants with lung injury from viral respiratory tract infection that was distinct from the T cell profile in circulation and associated with increasing disease severity. Airway sampling could therefore be diagnostically informative for assessing immune responses and lung damage.

Splenic priming of virus-specific CD8 T cells following influenza virus infection.

In healthy individuals, influenza virus (IAV) infection generally remains localized to the epithelial cells of the respiratory tract. Previously, IAV-specific effector CD8 T cells found systemically during the course of IAV infection were thought to have been primed in lung-draining lymph nodes with subsequent migration to other tissues. However, little is known about whether other lymphoid sites participate in the generation of virus-specific CD8 T cells during localized IAV infection. Here, we present evidence of early CD8 T cell priming in the spleen following respiratory IAV infection independent of lung-draining lymph node priming of T cells. Although we found early indications of CD8 T cell activation in the lymph nodes draining the respiratory tract, we also saw evidence of virus-specific CD8 T cell activation in the spleen. Furthermore, CD8 T cells primed in the spleen differentiated into memory cells of equivalent longevity and with similar recall capacity as CD8 T cells primed in the draining lymph nodes. These data showed that the spleen contributes to the virus-specific effector and memory CD8 T cell populations that are generated in response to respiratory infection.

Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets.

Knowledge of human T cells derives chiefly from studies of peripheral blood, whereas their distribution and function in tissues remains largely unknown. Here, we present a unique analysis of human T cells in lymphoid and mucosal tissues obtained from individual organ donors, revealing tissue-intrinsic compartmentalization of naive, effector, and memory subsets conserved between diverse individuals. Effector memory CD4(+) T cells producing IL-2 predominated in mucosal tissues and accumulated as central memory subsets in lymphoid tissue, whereas CD8(+) T cells were maintained as naive subsets in lymphoid tissues and IFN-γ-producing effector memory CD8(+) T cells in mucosal sites. The T cell activation marker CD69 was constitutively expressed by memory T cells in all tissues, distinguishing them from circulating subsets, with mucosal memory T cells exhibiting additional distinct phenotypic and functional properties. Our results provide an assessment of human T cell compartmentalization as a new baseline for understanding human adaptive immunity.