A large number of dendritic cell (DC) subsets have now been identified based on the expression of a distinct array of surface markers as well as differences in functional capabilities. More recently, the concept of unique subsets has been extended to the lung, although the functional capabilities of these subsets are only beginning to be explored. Of particular interest are respiratory DCs that express CD103. These cells line the airway and act as sentinels for pathogens that enter the lung, migrating to the draining lymph node, where they add to the already complex array of DC subsets present at this site. Here we assessed the contributions of these individual populations to the generation of a CD8 ؉ T-cell response following respiratory infection with poxvirus. We found that CD103 ؉ DCs were the most effective antigen-presenting cells (APC) for naive CD8 ؉ T-cell activation. Surprisingly, we found no evidence that lymph node-resident or parenchymal DCs could prime virusspecific cells. The increased efficacy of CD103؉ DCs was associated with the increased presence of viral antigen as well as high levels of maturation markers. Within the CD103 ؉ DCs, we observed a population that expressed CD8␣. Interestingly, cells bearing CD8␣ were less competent for T-cell activation than their CD8␣؊ counterparts. These data show that lung-migrating CD103 ؉ DCs are the major contributors to CD8 ؉ T-cell activation following poxvirus infection. However, the functional capabilities of cells within this population differ with the expression of CD8, suggesting that CD103 ؉ cells may be divided further into distinct subsets.

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■ AbstractAutoimmunity to islet cell antigens like glutamic acid decarboxylase 65kD (GAD65) is associated with the destruction of insulin-producing β-cells and progression to type 1 diabetes (T1D) in NOD mice and humans. T cell responses to GAD65 are detectable in the spleen of prediabetic NOD mice and in the peripheral blood of humans prior to the onset of overt hyperglycemia. Previous findings from our lab revealed that GAD65 546-554 -specific cytotoxic T lymphocytes (CTL) are present in naïve NOD mice and are able to induce islet inflammation upon adoptive transfer into NOD.scid recipients. Additionally, we found that professional antigen-presenting cells (APC) generate the p546-554 epitope from a soluble GAD65 fragment, p530-554, and from GAD65 released by injured β-cells in vivo. Here, we report that the GAD65 fragment p546-554 is a dominant CTL-inducing epitope which is naturally processed and presented by a GAD65-expressing β-cell line. Further, coculture of GAD65 546-554 -specific CTL with the β-cells leads to a reduction in insulin production and the induction of perforin-mediated cell death. Collectively, these findings support a role for the cross-presentation of GAD65 antigen in the priming and enhancement of dominant GAD65-specific CTL responses, which can directly target β-cells that display GAD65 epitopes.

A large number of viral infections are contracted via the respiratory route. Thus, an effective immune response at this site is of vital importance. Past studies in murine models analyzing a number of viruses have reported that CD8 1 effector T cells entering the lung after respiratory infection exhibit significant functional inactivation. The impaired function in these cells has been proposed to be the result of infection-induced changes in the lung; however, we have found that loss of function can occur in effector CD8 1 T cells present in the lung, even in the absence of infection. This functional inactivation takes place within 48 hours of entry into the lung, and is seen only in effector cells residing in the lung parenchyma, and not the airway. In this study, we have extended our findings to show that functional impairment of these effector cells is not initiated by bone marrow-derived cells, and is independent of proliferation in the lung tissue. Of critical importance, we have also determined that the susceptibility to functional inactivation is a common property shared by most effector cells. Finally, we show that the susceptibility to loss of function is actively regulated throughout differentiation. Although naive CD8 1 T cells, like effector cells, are negatively regulated as a result of residence in the lung, memory cells exhibit profound resistance to functional inactivation. The selective resistance of CD8 1 memory cells may allow the host to limit damage during the effector phase while retaining a protective response that can effectively limit subsequent infection.