Traditionally it has been thought that the capacity for immunological memory resides only in cells classified as part of the adaptive immune system: T cells and B cells. But over the past few years there have been hints that perhaps other cell types have the capacity to develop a memory phenotype. Most recently, a paper from Lewis Lanier’s laboratory has strongly suggested that natural killer (NK) cells can develop memory against murine CMV; transfer of the putative memory cells into naïve animals was shown to be protective against an MCMV challenge.
Now, the “Cutting Edge” section of the new issue of the Journal of Immunology contains the first report of possible NK memory in humans. The paper comes from Louise Kuhn’s research group, which has specialized in studying the factors associated with prevention of mother-to-child transmission (MTCT) of HIV. Kuhn and colleagues were initially studying HIV-specific CD4 and CD8 T cell responses in a cohort of mother-infant pairs (these data have been recently published in AIDS) when they identified cytokine responses to HIV peptides coming from non-T cells. Further investigations demonstrated that the cells were NK cells, and that the responses were primarily to peptides from HIV Env and Regulatory proteins.
The findings prompted the researchers to analyze whether the presence of the novel NK responses had any association with the risk of MTCT. The analysis revealed that 28 of 49 (57.1%) non-transmitting mothers and 13 of 44 (29.5%) uninfected infants had detectable responses. In stark comparison, only one of 15 (6.7%) transmitting mothers and one out of 18 (5.6%) of the infected infants displayed responses (p = 0.001 for mothers and p = 0.049 for infants).
In discussing their results, the authors write: “The absence of these responses among uninfected controls suggests that the responses are not due to a direct process of peptide binding to cell surface receptors and triggering of these innate immune cells. Their detection in the context of HIV-1 exposure among uninfected infants indicates that detectable antigenic load is not required in vivo. Taken together, these results support a hypothesis of a "memory" type response. If this is indeed found to be the case, this would represent the first such report that indicates the possibility of NK cell ‘memory’ in humans.”
Although it was written prior to the publication of Lewis Lanier’s MCMV data, an excellent background review on the possibility of NK cell memory can be found in the July 2006 IAVI Report. The article is written by Galit Alter and Marcus Altfeld, who are also actively exploring the subject in the context of HIV infection. Given the struggles to develop an HIV vaccine, the possibility of inducing novel memory responses against the virus surely deserves careful and urgent evaluation.
The Journal of Immunology, 2009, 182: 5914-5918.
Caroline T. Tiemessen2,*, Sharon Shalekoff*, Stephen Meddows-Taylor*, Diana B. Schramm*, Maria A. Papathanasopoulos, Glenda E. Gray¶, Gayle G. Sherman, Ashraf H. Coovadia and Louise Kuhn||
* AIDS Virus Research Unit, National Institute for Communicable Diseases, Department of Molecular Medicine and Haematology, University of the Witwatersrand Medical School; National Health Laboratory Services, Empilweni Clinic, Coronation Women and Children Hospital, Enhancing Childhood HIV Outcomes, University of the Witwatersrand, Johannesburg, South Africa; ¶ Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, Soweto, South Africa; and || Gertrude H. Sergievsky Center, College of Physicians and Surgeons and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032
Most infants exposed to HIV-1 in utero and at delivery do not acquire infection. We show that mothers and infants who have CD3-negative cells that respond to HIV-1 peptides are substantially less likely to transmit and acquire infection, respectively. The CD3-negative cells, shown to be NK cells, respond with remarkable specificity and high magnitude to HIV-1 peptides from Env (envelope) and Reg (regulatory) protein regions, as measured by a whole blood intracellular cytokine assay only in the context of HIV-1 infection or exposure. These findings identify an important new measure of protective immunity to HIV-1 that highlights the importance of innate immunity in preventing the establishment of HIV-1 infection.