TRAIL deficiency delays, but does not prevent, erosion in the quality of "helpless" memory CD8 T cells.

In this study, we investigated the role of TRAIL in Ag-specific CD8 T cell homeostasis after viral infection. TRAIL deficiency does not influence the kinetics of the Ag-specific CD8 T cell responses, and CD8 T cells in TRAIL-deficient mice were able to expand, contract, and generate functional memory cell numbers that were indistinguishable from TRAIL-sufficient wild-type CD8 T cells after acute lymphocytic choriomeningitis virus infection. Interestingly, the ability of "helpless" CD8 T cells to retain their memory phenotypic and functional (i.e., secondary expansion) characteristics was prolonged in TRAIL-deficient mice compared with wild-type CD4-depleted controls. However, TRAIL deficiency only delayed, but did not prevent, the eventual erosion in the quality of helpless memory CD8 T cells, and that correlated with their inability to respond to a second round of Ag-driven proliferation. These data, which suggest that CD4 help consists of both TRAIL-dependent and -independent components, may help to resolve the current controversy between the early programming and maintenance models that were put forward to explain the role of CD4 T cell help in Ag-specific CD8 T cell homeostasis.

MHC class Ia-restricted memory T cells inhibit expansion of a nonprotective MHC class Ib (H2-M3)-restricted memory response.

Listeria monocytogenes infection generates major histocompatibility complex (MHC) class Ia-restricted and MHC class Ib-(H2-M3)-restricted effector and memory CD8+ T cells. However, only MHC class Ia-restricted memory cells expand after rechallenge, and it is unknown if MHC class Ib-restricted memory CD8+ T cells generated by vaccination are protective. We show here that H2-M3-restricted memory CD8+ T cells were capable of secondary expansion but, in contrast to primary H2-M3-restricted effector cells, failed to provide protective immunity. In lm-immune mice, MHC class Ia-restricted memory CD8+ T cells prevented the expansion of H2-M3-restricted memory T cell populations by limiting dendritic cell antigen presentation. Thus, protective immunity by H2-M3-restricted T cells is limited to primary infection, indicating that memory MHC class Ia-restricted T cells prevent nonessential immune responses during secondary infection.

Deficient anti-listerial immunity in the absence of perforin can be restored by increasing memory CD8+ T cell numbers.

Compared with wild-type (WT) mice, Listeria monocytogenes (LM)-vaccinated perforin-deficient (PKO) mice have elevated levels of CD8(+) T cell memory, but exhibit reduced levels of protection against virulent LM. In this study, Ag-specific CD8(+) T cells from LM-vaccinated WT and PKO mice were used in adoptive transfer assays to determine the contribution of perforin-dependent cytolysis in protective immunity to LM. Perforin deficiency resulted in an approximately 5-fold reduction in the per-cell protective capacity of Ag-specific memory CD8(+) T cells that was not caused by differences in memory cell quality as measured by CD62L/CD27 expression, TCR repertoire use, functional avidity, differences in expansion of Ag-specific cells upon infection, or maintenance of memory levels over time. However, perforin-deficient CD8(+) T cells exhibited reduced in vivo cytotoxic function compared to WT CD8(+) T cells. Consistent with the existence of perforin-independent effector pathways, double-vaccinated PKO mice were as resistant to challenge with LM as single-vaccinated WT mice. Thus, increasing the number of memory CD8(+) T cells can overcome diminished per-cell protective immunity in the absence of perforin.

Regulation of CD8+ T cells undergoing primary and secondary responses to infection in the same host.

Naive Ag-specific CD8(+) T cells expand, contract, and become memory cells after infection and/or vaccination. Memory CD8(+) T cells provide faster, more effective secondary responses against repeated exposure to the same pathogen. Using an adoptive transfer system with low numbers of trackable nontransgenic memory CD8(+) T cells, we showed that secondary responses can be comprised of both primary (naive) and secondary (memory) CD8(+) T cells after bacterial (Listeria monocytogenes) and/or viral (lymphocytic choriomeningitis virus) infections. The level of memory CD8(+) T cells present at the time of infection inversely correlated with the magnitude of primary CD8(+) T cell responses against the same epitope but directly correlated with the level of protection against infection. However, similar numbers of Ag-specific CD8(+) T cells were found 8 days postinfection no matter how many memory cells were present at the time of infection. Rapid contraction of primary CD8(+) T cell responses was not influenced by the presence of memory CD8(+) T cells. However, contraction of secondary CD8(+) T cell responses was markedly prolonged compared with primary responses in the same host mice. This situation occurred in response to lymphocytic choriomeningitis virus or L. monocytogenes infection and for CD8(+) T cell responses against multiple epitopes. The delayed contraction of secondary CD8(+) T cells was also observed after immunization with peptide-coated dendritic cells. Together, the results show that the level of memory CD8(+) T cells influences protective immunity and activation of naive precursors specific for the same epitope but has little impact on the magnitude or program of the CD8(+) T cell response.

Alcohol, injury, and cellular immunity.

It is widely accepted that alcohol exposure is a causative factor in the occurrence of burn or other traumatic injury. It is less well known that individuals who have consumed alcohol before sustaining an injury suffer from increased morbidity and mortality compared with the morbidity and mortality of non-alcohol-consuming subjects with similar injuries. Complications due to bacterial infection are the most common burn sequelae in injured patients and are frequently associated with depressed immunity. Independently, alcohol exposure and injury have been shown to influence cellular immunity negatively. These changes in immunity are closely linked to injury- or alcohol-induced alterations in the cytokine milieu in both clinical studies and animal models. Not surprisingly, the combination of insult of alcohol exposure and burn injury results in immune suppression that is greater in magnitude and duration compared with either insult alone. The combined effects of alcohol and injury on immunity have been examined in a limited number of studies. However, results of these studies support the suggestion that altered cytokine production is an integral part of the immune dysregulation and increased mortality that is observed. In particular, the increased presence of macrophage-derived mediators observed after burn or alcohol exposure alone seems to be synergistically increased in a combined injury model. Although more research is needed, it is likely that therapeutic modalities that include manipulation of cytokine networks to boost cellular immunity may improve outcome for patients who sustain injuries subsequent to consuming alcohol.