Tight Regulation of Memory CD8+ T Cells Limits Their Effectiveness during Sustained High Viral Load

Abstract

Summary To design successful vaccines for chronic diseases, an understanding of memory CD8+ T cell responses to persistent antigen re-stimulation is critical. However, most studies comparing memory and naïve cell responses have only been performed in rapidly cleared acute infections. Herein, by comparing the responses of memory and naïve CD8+ T cells to acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we show that memory cells dominated over naïve cells and were protective when present in sufficient numbers to quickly reduce infection. In contrast, when infection was not rapidly reduced, memory cells were quickly lost, unlike naïve cells. This occurred with both transgenic and endogenous memory CD8+ T cells, and with memory cells initially generated by different vaccines. This loss of memory cells was due to a block in sustaining cell proliferation, selective regulation by the inhibitory receptor 2B4, and increased reliance on CD4+ T cell help. Thus, emphasizing the importance of designing vaccines that elicit effective CD4+ T cell help and rapidly control infection.

Memory CD8+T Cells Specific for a Single Immunodominant or Subdominant Determinant Induced by Peptide-Dendritic Cell Immunization Protect from an Acute Lethal Viral Disease

“…We observed complete protection only when the frequency of memory CD8 ϩ T cells was high. In agreement with our findings, West et al demonstrated that a high frequency (10 5 ) of virus-specific memory CD8 ϩ T cells from P14 transgenic mice were able to rapidly reduce or clear LCMV clone 13 virus (55). Thus, independent of the reason for the inability of ITYRFYLI-and STLNFNNL-pulsed DCs to induce a response, our data suggest that protection strongly correlates with productive immunization and that the immunogenicity of a peptide may vary with the method of immunization.…”

Aging promotes acquisition of naive-like CD8+ memory T cell traits and enhanced functionalities

“…Such observations certainly underscore the challenges associated with the definition of general principles applicable to T cell-mediated immune protection, but it should also be noted that clinically relevant differences (e.g., the level of infectious pathogen) may emerge at times only under very specific experimental conditions (e.g., the "right" combination of transferred CD8 + T M numbers, pathogen challenge dosage, and timing of analyses). Therefore, a combinatorial analysis of such experimental parameters will be particularly informative (52).…”

Multiple Layers of CD80/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity

“…Short-term stimulation cultures (5 h) with LCMV-GPand -NP-derived peptides (CD8 ϩ T cell determinants, GP 33 , GP 92 , GP 118 , GP 276 , NP 205 , and NP 396 ; CD4 ϩ T cell determinants, GP 64 and NP 309 ) in the presence of the protein transport inhibitor brefeldin A (BFA) were performed as described previously (39) to evaluate inducible T cell functionalities. Please note that the CD4 ϩ T cell population specific for the I-A b -restricted GP [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] determinant also reacts with longer (GP 61-80 ) and shorter (GP [66][67][68][69][70][71][72][73][74][75][76][77] ) versions of this epitope (37).…”