Immunological memory, the ability to make enhanced responses to re-encountered Ags, is a defining feature of the adaptive immune system. After initial foreign Ag exposure (delivered in a suitably immunogenic form), immunological memory can persist for life, generating the state we typically consider as “immune.” But what maintains immune memory? This question is of tremendous relevance for vaccine design, where induction of durable (preferably life-long) protective immunity is the quintessential goal. At the same time, disrupting selective memory responses might prevent immunopathological secondary responses (1) and potentially be used to treat certain autoimmune diseases.

Perhaps the most controversial issue in understanding the basis for immune memory has been the role of foreign Ag. This issue is not limited to chronic infections; the finding that Ag/Ab complexes can be maintained long-term on the surface of follicular dendritic cells (2, 3) suggested that any Ag (e.g., from an acute infection or subunit vaccine) might be maintained and impact the persistence of memory.

This led to the question of whether an Ag depot was involved in maintenance of T cell memory. Impressive studies in the early 1990s suggested this was indeed the case (4, 5). The essential approach was to transfer T cells from immunized animals into various recipients, followed by assessment of donor T cell reactivity toward Ag. Donor memory cells placed in unimmunized hosts could mount a secondary response at first, but recall activity declined dramatically within weeks (4) or even days (5) after transfer. Such loss of recall reactivity could be avoided by renewing foreign Ag exposure (4). These studies involved both CD4+ and CD8+ T cell responses (mounted against model foreign Ags, histocompatibility proteins, or infectious agents), and the similar conclusions strongly suggested that something persisting in the primed environment (most likely foreign peptide/MHC complexes) was essential for effective durability of T cell memory.

One might quibble that memory requiring constant reminding (a situation parents may recognize in teenagers) is not really “memory” at all; still, the model had appeal on theoretical grounds. A fundamental question about immunological memory is how it resists erosion by subsequent immune responses; that is, if one assumes that the size of the memory pool is fixed (we will come back to that), homeostasis would demand that new memory cells displace old ones (6). The capacity to sustain treasured memories by regular encounter with a foreign Ag depot nicely resolves this issue.

However, the situation changed abruptly in 1994, with the appearance of the current Pillars of Immunology article from Rafi Ahmed’s group (7). Lau et al. (7) primed mice with an acute lymphocytic choriomeningitis virus (LCMV) infection, allowed the response to reach memory stage (>3 mo), and then adoptively transferred enriched CD8+ T cells into uninfected host mice. Realizing that any viral transfer would compromise interpretation, the investigators took pains to show that there was no detectable virus in the inoculum, and that the host lymphocytes never mounted an LCMV-specific immune response. Using laborious limiting dilution assays (remember, this work was years before development of peptide/MHC tetramers; see Ref. 8), the authors tracked the maintenance of LCMV-specific donor CD8+ T cells over time.

The results were clear and spectacular: for 18 mo following transfer into uninfected mice, the LCMV-specific memory CD8+ T cell numbers hardly changed. This durability was essentially identical to that seen in intact immunized mice, suggesting that removal from any (putative) source of persisting Ag had no impact on memory maintenance.

Apparently not satisfied with a 1.5 y time point, Lau et al. (7) performed another adoptive transfer of the remaining CD8+ T cells into new uninfected recipients and examined memory maintenance 8 mo later. Even at this (26 mo) time point, the number of virus-specific memory CD8+ T cells was maintained. It's worth realizing that these T cells were assayed 29 months from the initial infection: longer than most mice live.

However, these assays only measured memory cell maintenance. What about protective function? To test this, Lau et al. assessed clearance of an LCMV challenge by immune CD8+ T cells transferred into unimmunized hosts 15 mo earlier. Once again, the data were clear: memory cells maintained in unimmunized hosts showed robust control of the LCMV infection.

Simultaneously, Doherty and colleagues (9) and Mullbacher (10) showed similar evidence for memory CD8+ T cell persistence in the absence of foreign Ag (albeit without evaluating in vivo protective immunity) in distinct viral models.

So, did these findings resolve the issue? Although the data were compelling, controversy continued for many years (6, 11, 12). Use of irradiated recipients in Lau et al.’s transfer experiments raised questions about whether T cell lymphopenia drove nonphysiological memory maintenance. Furthermore, these studies could not exclude a role for cross-reactive foreign Ag (e.g., from a subsequent infection) in LCMV-specific memory maintenance. Such debates percolated through the literature until Ahmed’s group (13) published the dramatic finding that memory CD8+ T cell maintenance did not even require expression of MHC class I molecules (tightening the evidence from previous studies; see Ref. 9), including experiments that avoided use of irradiated recipients altogether (13). The conclusion that memory CD8+ T cell maintenance was independent of typical TCR ligands effectively silenced most critics.

Other surprises have since emerged, including the unexpected finding that homeostatic processes can drive production of long-lived memory T cells in the apparent absence of any foreign Ag encounter whatsoever (14). Also, studies showing that the size of the memory CD8+ T cell pool is pliable, increasing to accommodate an enlarged memory pool (15), suggest that competition within the memory pool is not as ruthless as first thought.

At the same time, the report from Lau et al. and numerous subsequent studies indicate that T cell memory can persist without foreign Ag; however, this does not mean it always will or that this is the best way to preserve functional immunity. Whereas Lau et al. focused on CD8+ T cell responses, CD4+ T cell memory seems far less durable following an acute infection (16, 17). Interestingly, persistent Ag can, in at least some situations, sustain CD4+ T cell memory. This was dramatically illustrated by studies on Leishmania in mice, where it was found that persistence of Ag (in the form of a depot of parasite maintained at the original site of infection) was required for maintenance of resistance to new infections by the parasite (a situation called concomitant immunity) (18). Hence, in this and related models (19), persistence of foreign Ag (the live pathogen, in fact) is required for both preservation of T cell memory and protective immunity.

Furthermore, some viruses establish latent infections, which cause intermittent restimulation of the immune response and can lead to sustained high levels of Ag-specific memory CD8+ T cells (20). Such populations typically hold potentially lethal infections (such as EBV and CMV) at bay, and they show promise as a novel approach for an HIV vaccine (21). However, foreign Ag persistence is a two-edged sword: certain chronic infections can cause functional exhaustion and/or physical deletion of Ag-specific T cells (20). Hence, depending on the nature of a given pathogen, persisting foreign Ags can be irrelevant, helpful, or detrimental for memory maintenance.

Finally, it is worth recalling that persistence of memory T cells does not automatically mean persistence of immunity. Some reports showed a decline in protection, despite maintenance of Ag-specific CD8+ T cell numbers, after immunization (22). Subsequent understanding that there are distinct memory CD8+ T cells with diverse protection and maintenance characteristics (23) may well explain such findings, especially in situations where immune memory is limiting.

This landmark report by Lau et al. compellingly demonstrated the profound durability of memory CD8+ T cells following a transient encounter with foreign Ag. The stage was set for defining the factors, such as IL-15 (24), that are involved in memory CD8+ T cell maintenance and the manner in which effector and memory fates become fixed in the responding T cell population (25, 26).

Abbreviation used in this article:

LCMV

lymphocytic choriomeningitis virus.

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The author has no financial conflicts of interest.