CD40-deficient, Influenza-specific CD8 Memory T Cells Develop and Function Normally in a CD40-sufficient Environment

154

125

The fate of naive CD8+ T cells is determined by the environment in which they encounter MHC class I presented peptide Ags. The manner in which tumor Ags are presented is a longstanding matter of debate. Ag presentation might be mediated by tumor cells in tumor draining lymph nodes or via cross-presentation by professional APC. Either pathway is insufficient to elicit protective antitumor immunity. We now demonstrate using a syngeneic mouse tumor model, expressing an Ag derived from the early region 1A of human adenovirus type 5, that the inadequate nature of the antitumor CTL response is not due to direct Ag presentation by the tumor cells, but results from presentation of tumor-derived Ag by nonactivated CD11c+ APC. Although this event results in division of naive CTL in tumor draining lymph nodes, it does not establish a productive immune response. Treatment of tumor-bearing mice with dendritic cell-stimulating agonistic anti-CD40 mAb resulted in systemic efflux of CTL with robust effector function capable to eradicate established tumors. For efficacy of anti-CD40 treatment, CD40 ligation of host APC is required because adoptive transfer of CD40-proficient tumor-specific TCR transgenic CTL into CD40-deficient tumor-bearing mice did not lead to productive antitumor immunity after CD40 triggering in vivo. CpG and detoxified LPS (MPL) acted similarly as agonistic anti-CD40 mAb with respect to CD8+ CTL efflux and tumor eradication. Together these results indicate that dendritic cells, depending on their activation state, orchestrate the outcome of CTL-mediated immunity against tumors, leading either to an ineffective immune response or potent antitumor immunity.

Section: Discussioncontrasting

confidence: 71%

Activation of Dendritic Cells That Cross-Present Tumor-Derived Antigen Licenses CD8+ CTL to Cause Tumor Eradication

Mierlo¹,

Boonman

Dumortier³

et al. 2004

154

125

“…However, some primary CD8 T cell responses to pathogens such as adenovirus (19), influenza virus (20), HSV-1 (21), and L. monocytogenes (22), are CD4 T cell help dependent. Because direct CD40-CD40L interaction between CD8 and CD4 T cells is not involved in these infections (34,35), it has been unclear why CD4 T cell help is needed in these settings. Our results presented here demonstrate that CD4 T cell help is also required for primary CD8 T cell response to VV infection in vivo.…”

Section: Discussionmentioning

confidence: 99%

CD4 T Cells Are Required for CD8 T Cell Survival during Both Primary and Memory Recall Responses

Novy

Quigley

Huang³

et al. 2007

122

123

The role of CD4 T cell help in primary and secondary CD8 T cell responses to infectious pathogens remains incompletely defined. The primary CD8 T response to infections was initially thought to be largely independent of CD4 T cells, but it is not clear why some primary, pathogen-specific CD8 T cell responses are CD4 T cell dependent. Furthermore, although the generation of functional memory CD8 T cells is CD4 T cell help dependent, it remains controversial when the “help” is needed. In this study, we demonstrated that CD4 T cell help was not needed for the activation and effector differentiation of CD8 T cells during the primary response to vaccinia virus infection. However, the activated CD8 T cells showed poor survival without CD4 T cell help, leading to a reduction in clonal expansion and a diminished, but stable CD8 memory pool. In addition, we observed that CD4 T cell help provided during both the primary and secondary responses was required for the survival of memory CD8 T cells during recall expansion. Our study indicates that CD4 T cells play a crucial role in multiple stages of CD8 T cell response to vaccinia virus infection and may help to design effective vaccine strategies.

“…However, a number of reports have also demonstrated that CD40 is dispensable for the development of functional CD8 ϩ T cell memory upon immunization with virus-like particles or infection with other viruses or bacteria (31)(32)(33)(34).…”

Section: F Ollowing Exposure To Ag Naive Cd8mentioning

confidence: 99%

CD40 on APCs Is Needed for Optimal Programming, Maintenance, and Recall of CD8+ T Cell Memory Even in the Absence of CD4+ T Cell Help

Hernandez

Shen²,

Rock³

2008

CD40 stimulation is one of the many signals that can activate APCs and we have recently shown it to have a unique function in generating maximum primary CD8+ T cell responses. However, whether CD40 signaling plays a role in memory CD8+ T cell responses is still not completely understood. In this study, we show that in the absence of CD40 on all APCs or specifically on dendritic cells, memory CD8+ T cells are generated but at significantly reduced levels. This reduction is due to a contribution of CD40 at several different steps in the generation of CD8+ memory. In the initial T cell response, CD40 contributes to maximizing not only the number of effector cells that are generated but also the programming of ones that will differentiate into memory. Subsequently, CD40 is needed to maintain maximal numbers of the committed memory cells in a manner that is independent of the immunizing Ag. Finally, when memory CD8+ T cells are reactivated there is a variable requirement for CD40 depending on whether CD40 or CD4+ Th cells were present during the primary response. Therefore, CD40 signaling on APCs plays an important role in all phases of a memory CD8+ T cell response.