Memories that last forever: strategies for optimizing vaccine T-cell memory

Abstract

For acute self-limiting infections a vaccine is successful if it elicits memory at least as good as the natural experience; however, for persistent and chronic infections such as HIV, hepatitis C virus (HCV), human papillomavirus (HPV), and human herpes viruses, this paradigm is not applicable. At best, during persistent virus infection the person must be able to maintain the integrity of the immune system in equilibrium with controlling replicating virus. New vaccine strategies are required that elicit both potent high-avidity CD8 ؉ T-cell effector/memory and central memory responses that can clear the nidus of initial virus-infected cells at mucosal surfaces to prevent mucosal transmission or significantly curtail development of disease. The objective of an HIV-1 T-cell vaccine is to generate functional CD8 ؉ effector memory cells at mucosal portals of virus entry to prevent viral transmission. In addition, long-lived CD8 ؉ and CD4 ؉ central memory cells circulating through secondary lymphoid organs and resident in bone marrow, respectively, are needed to provide a concerted second wave of defense that can contain virus at mucosal surfaces and prevent systemic dissemination. Further understanding of factors which can influence long-lived effector and central memory cell differentiation will significantly contribute to development of effective T-cell vaccines. In this review we will focus on discussing mechanisms involved in T-cell memory and provide promising new approaches toward expanding current vaccine strategies to enhance antiviral memory. (Blood. 2010;115:1678-1689) IntroductionA common defining characteristic of immune memory is that it is both selective and parsimonious. After resolution of primary infection a small somewhat constant fraction of cells remain depending upon initial precursor frequency and the balance between T-cell receptor (TCR) signal strength and prosurvival signals received. 1,2 Memory cells are homeostatically maintained in a progrowth state poised to respond rapidly to secondary infection. The fidelity of memory and effectiveness to thwart disease is reflected in the multifunctional character of the recalled response. Memory T cells are heterogenous in terms of phenotype, function, and anatomical locations. [3][4][5] Understanding cytokine and costimulatory signals that influence transcriptional programs regulating T-cell differentiation and memory is key to manipulating vaccine responses. Furthermore, defining different subpopulations of memory CD8 ϩ T cells by differentiation and activation markers representative of transcriptional programs associated with protective recall responses will be key to predicting vaccine efficacy.To date, strategies for targeted delivery of vaccines and inclusion of cytokines, chemokines, and immunomodulatory molecules for enhancing the magnitude of immune responses and memory have been mostly empirical. For HIV-1 vaccines this has involved the expression of HIV-1 genes, cytokines, and chemokines by in vivo delivery of plasmid DNA and recombinant v...

Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue

“…12,13 IL-7 and IL-7R may play a role in Mycobacterium tuberculosis (Mtb) infection at different levels: IL-7 drives maturation of antigen-presenting cells and ensures T-cell survival, 14,15 whereas passive transfer of Mtb-reactive immune cells from IL-7-treated mice have been shown to prolong survival and reduce pulmonary Mtb load in mice. 16 The IL-7R is expressed by a variety of immune 17,18 and non-immune cells, 7,10 either along with the common cytokine g-chain 19 or the receptor for thymic stromal lymphopoietin on dendritic cells.…”

Stimulation through very late antigen‐4 and ‐5 improves the multifunctionality and memory formation of CD8+ T cells

“…It would be intriguing to address the differential involvement of molecules reported to play important roles in memory formation, such as Blimp-1, mTOR, T-bet, eomesodermin, Bcl-6, and Id2, in the VLA-4/5-mediated signaling pathway [28,29]. The importance of VLA-4/5 in the formation of T-cell memory under physiological conditions such as microbial infection or spontaneous tumor development is a topic for future investigations, although our results suggest that these integrins play a positive role in this process.…”

Is the choice of vaccine adjuvant critical for long-term memory development?

“…By contrast, CD72 has been found to be a relatively good marker for memory B cells in humans, although it appears that not all CD72 + cells are memory cells and that CD27 -memory B cells have also been identified [14]. The corresponding markers for CD4 + T cells are CD44 + , CCR7 -and CD62L -(for effector memory) and CD44 + , CCR7 + and CD62L + (for central memory) cells [15]. Identifying the magnitude and tissue distribution of specific memory T and B cells could be another critical component for assessments of vaccine efficacy with regard to a long-term protective effect [16].…”