From vaccines to memory and back

Abstract

Vaccines work by eliciting an immune response and consequent immunological memory that mediates protection from infection or disease. Recently, new methods have been developed to dissect the immune response in experimental animals and humans, which have led to increased understanding of the molecular mechanisms that control differentiation and maintenance of memory T and B cells. In this review we will provide an overview of the cellular organization of immune memory and underline some of the outstanding questions on immunological memory and how they pertain to vaccination strategies. Finally we will discuss how we can learn about antigen design from the interrogation of our memory T and B cells-a journey from vaccines to memory and back.

Figure 1. T cell migration to the gut

Effector CD8 T cells activated in lymphoid tissues transiently express gut homing receptors ( a4b7 , CCR9 ) and migrate to the intestinal mucosa. These T cells then undergo a distinct memory differentiation program within the gut and do not recirculate with memory T cells in other tissues. These tissue resident memory cells provide a first line of defense against pathogens that initiate infection through the intestinal mucosa.

Figure 2. Using the principles of memory T cell differentiation to determine the optimal time for boosting

(A) Following primary vaccination naïve T cells proliferate and differentiate into effector cells. The majority of these effectors undergo apoptosis but a subset further differentiates to form the pool of long-lived memory cells. This model of progressive memory T cell differentiation is characterized by a gradual acquisition of memory T cell properties such as the ability to make effective proliferative responses upon re-encounter with antigen. (B) Based on this memory differentiation program the optimal time for boosting is during the late stages of the effector to memory transition and therefore an interval of 2–3 months is recommended between the prime and the boost.

Figure 3. Repeated immunizations drive memory T cells towards terminal differentiation: Implications for memory cell heterogeneity and protective immunity

(A) Repetitive antigen encounter results in memory T cells with more effector-like properties and with preferential location in non-lymphoid tissues but with reduced proliferative potential. (B) If all memory T cells are recruited into the response following each booster shot then the entire pool of memory T cells would be driven towards terminal differentiation. (C) If only some of the memory T cells are activated upon subsequent booster immunizations then one would end up with a heterogenous pool of memory T cells with both effectorlike cells at mucosal sites and also memory cells with proliferative capacity.

Figure 4. Using drugs to modulate memory CD8 T cell differentiation

(A) Antigen specific CD8 T cell responses after an acute infection or vaccination. During the expansion phase, naïve CD8 T cells proliferate and then become effector cells. After clearance of the pathogen, 90 to 95% of the effector T cells die during a contraction phase. The surviving 5–10% of the antigen-specific T cells become the memory population. (B) Without rapamycin treatment. (C) Rapamycin improves both quality and quantity of memory CD8 T cells. Rapamycin treatment increases memory precursor effector cells that survive during the contraction phase, and also improves quality of memory T cells by accelerating effector to memory T cell formation.

Figure 5. The use of high throughput cellular screens to inform vaccine design

(A) Memory B and T cells can be isolated according to the expression of surface markers and cultured in limiting dilution conditions to assess specificity, phenotype and function of individual cells. Specific antibodies can be retrieved by memory B cell immortalization or by amplification of the V region genes from single cells. T cells libraries can be screened in an iterative fashion to determine fine specificity and to isolate T cell clones. (B) Naïve T cells stimulated in vitro with monocytes or DC and whole pathogens recapitulate the phenotype of ex vivo isolated memory T cells.