In the new issue of Immunity, Rafi Ahmed and colleagues from Emory University's Vaccine Center offer a detailed analysis of both the acute and memory CD8 T cell responses to two highly efficacious vaccines: yellow fever (YFV) and Dryvax (smallpox vaccine). Both vaccines induced vigorous CD8 T cell activation that peaked around two weeks after administration. Activated CD8 T cells (assessed by a combination of markers include CD38, HLA-DR, Ki-67 and Bcl-2) represented 12-40% of peripheral blood CD8 T cells at this timepoint. The authors estimate that each virus-specific naïve CD8 T cell responding to the vaccines likely divided 16-20 times, a finding that echoes estimates from murine studies (which have suggested each responsive naïve CD8 T cells undergoes around 15 divisions). This represents a 10,000-100,000-fold expansion of each virus-specific CD8 T cell.
With both vaccines, the CD8 T cell response declined sharply after the peak and levels of activated CD8 T cells were close to pre-vaccination levels by day 30, consistent with the contraction phase that accompanies the development of long-term memory responses. Analysis of several phenotypic markers suggested that the differentiation of the memory CD8 T cell response was prolonged; for example, granzyme B and CCR5 expression was clearly further reduced between days 28 and 84 after immunization, while CD45RA expression continued to increase. These data are likely relevant for the selection of optimal immunization schedules for T cell-based vaccines.
Although some decline in memory CD8 T cell responses was evident over the 2 years after vaccination, the researchers calculated that these responses would persist at substantial levels for at least 20 years; a separate analysis showing detectable memory CD8 T cell responses to Dryvax in individuals who received the vaccine ~50 years ago is cited in support of this extrapolation. In terms of magnitude, memory CD8 T cell responses to YFV were around 200-600 spot-forming cells per million PBMC at the 1 year post-immunization timepoint. Long-term memory CD8 T cells were also shown to proliferate robustly and produce interferon-gamma and IL-2 in response to in vitro restimulation, 2 years after vaccination.
One interesting observation that is highlighted in the accompanying commentary by Walker & Slifka is that only a minority of the activated effector CD8 T cells present at the peak of the acute response could be formally demonstrated to be vaccine-specific, even though analysis of T cells of other specificities offered no evidence of "bystander" activation. This finding echoes that of a prior analysis of CD4 T cell responses to Dryvax published by John Zaunder and colleagues. In both cases, these T cells express high levels of the activation marker CD38. One of the ongoing mysteries of HIV pathogenesis is the presence of elevated levels of CD38-expressing CD8 and CD4 T cells, the specificity of which has remained elusive for over two decades now. One possibility raised by these studies is that these activated T cells in HIV infection are in fact virus-specific, but represent newly generated HIV-specific naive T cells that are activated by HIV antigens in overlapping waves after exiting the thymus. While the daily output of HIV-specific naive T cells would be expected to be low in chronic infection, recent studies have shown rare naive T cells can expand prodigiously upon activation.
The paper is advertised on the Immunity website as free access but I was unable to find a link to the full text that did not redirect to the Science Direct library which then asks for $31.50; hopefully this problem will soon be fixed.
Immunity, Vol 28, 710-722, 16 May 2008
Human Effector and Memory CD8+ T Cell Responses to Smallpox and Yellow Fever Vaccines
Joseph D. Miller,1,2 Robbert G. van der Most,1,2 Rama S. Akondy,1 John T. Glidewell,1 Sophia Albott,1 David Masopust,1 Kaja Murali-Krishna,1 Patryce L. Mahar,1 Srilatha Edupuganti,1 Susan Lalor,1 Stephanie Germon,1 Carlos Del Rio,1 Mark J. Mulligan,1 Silvija I. Staprans,1,3 John D. Altman,1 Mark B. Feinberg,1,3 and Rafi Ahmed1,
1 Emory Vaccine Center and the Hope Clinic, Emory University School of Medicine, Atlanta, GA 30322, USA
To explore the human T cell response to acute viral infection, we performed a longitudinal analysis of CD8+ T cells responding to the live yellow fever virus and smallpox vaccines—two highly successful human vaccines. Our results show that both vaccines generated a brisk primary effector CD8+ T cell response of substantial magnitude that could be readily quantitated with a simple set of four phenotypic markers. Secondly, the vaccine-induced T cell response was highly specific with minimal bystander effects. Thirdly, virus-specific CD8+ T cells passed through an obligate effector phase, contracted more than 90% and gradually differentiated into long-lived memory cells. Finally, these memory cells were highly functional and underwent a memory differentiation program distinct from that described for human CD8+ T cells specific for persistent viruses. These results provide a benchmark for CD8+ T cell responses induced by two of the most effective vaccines ever developed.
Immunity, Vol 28, 604-606, 16 May 2008
Preview
The Immunostimulatory Power of Acute Viral Infection
Joshua M. Walker1 and Mark K. Slifka1
1 Vaccine and Gene Therapy Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006
In this issue of Immunity, Miller et al., 2008 use multiple independent techniques to demonstrate that antiviral T cell responses after acute human infection are much larger than previously realized.
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