Barbara Shacklett, Ph.D.
Professor
3327 Tupper Hall
Davis Campus
530-752-6785
e-mail

Areas of investigation

Our research group focuses on cell-mediated immune responses to HIV and other viruses in mucosal tissues, and trafficking of lymphoid cells to mucosal tissues and the central nervous system.

Significance

Most studies of antiviral immunity have focused on peripheral blood. However, the majority of lymphocytes are harbored in lymphoid tissues throughout the body. Mucosal lymphoid tissues serve as a portal of entry for HIV and as a site of active viral replication and CD4+ T-cell depletion. Therefore, studies of mucosal immunity are of particular importance for our understanding of HIV pathogenesis. Understanding the induction of antiviral immunity at mucosal surfaces is also of great relevance for vaccine development, as the majority of HIV transmission occurs through sexual contact.

Approaches

We have established methods to detect antigen-specific T cells in mucosal tissues using clinical samples obtained by minimally invasive methods. We use a combination of approaches including flow cytometry, cellular immunology, and molecular biology, to study the trafficking patterns and effector functions of antigen-specific T cells. These translational research projects involve active collaborations with clinicians at UC Davis Medical Center and the University of California, San Francisco.

Contributions

  • Development of methods and approaches to study antiviral immunity in mucosal tissues during natural infection (i.e., HIV) and after vaccination
  • Identification of HIV and CMV-specific CD8+ T cells in gut-associated lymphoid tissue
  • Development of live, attenuated simian immunodeficiency viruses to study correlates of protective immunity to HIV/SIV in nonhuman primates

Questions addressed in ongoing studies

  • What are the effector functions of antiviral T-cells in mucosal tissues?
  • What is the relationship between CD8+ T cell frequency and HIV viral load in tissues?
  • What molecules (i.e., integrins, chemokines) are involved in the trafficking of antigen-specific T cells to mucosal tissues and to the central nervous system?
  • How do immunization routes correlate with the induction of antiviral T cell responses in tissues?

Kiniry, B.E., Hunt, P.W., Hecht, F.M., Somsouk, M., Deeks, S.G., and Shacklett, B.L. (2018), Differential expression of CD8+ T-cell cytotoxic effector proteins in blood and gastrointestinal mucosa in HIV-1 infection. Journal of Immunology 200(5):1876-1888. PMC5821568. This article was highlighted in the journal section “In This Issue”: Peculiar Function of Rectosigmoid CD8+ T-cells in HIV. Journal of Immunology, 200:1531-1532.

Shacklett, B.L. (2018), Mucosal immunity to HIV-1: T-cells, B-cells, and beyond, Invited Review for Current Immunology Reviews. In press.

Kiniry, B.E., Ganesh, A., Li, S., Hunt, P.W., Somsouk, M., Skinner, P., Deeks, S.G., and Shacklett, B.L. (2018), Identification of HIV-1-specific tissue resident memory CD8+ T-cells in chronic infection. Mucosal Immunology, 11(3):909-920. doi:10.1038/mi.2017.96. PMC5953759.

Shacklett B, Derdeyn, C.A., Folayan, M.O., Landovitz, R.J., Anthony, C., Behrens, A.J., Hope, T.J., Landais, E., Leal L., Marrazzo, J.M., Morris, L., Mugo, N., Ngure, K., Noseda, V., Ranasinghe, S., Tully, D.C., Voronin, Y., Warren, M., Wibmer, C.K., Xie, I.Y., Scarlatti, G., and Thyagarajan, B. (2017), HIVR4P 2016, Partnering for Prevention: Conference Summary and Highlights. AIDS Research and Human Retroviruses 33(8):749-759. PMC5564036. (Recognized by the journal as its 9th most downloaded paper in 2017).

Owen, B.N., Elmes, J., Silhol., R., Dang, Q., McGowan, I., Shacklett, B., Swann, E.M., van der Straten, A., Baggaley, R.F., and Boily, M.-C. (2017), How common and frequent is heterosexual anal intercourse among South Africans? A systematic review and meta-analysis. Journal of the International AIDS Society, 19(1):1-14. PMC5461120.

Chang, W.L., Gonzalez, D.F., Kieu, H.T., Castillo, L.D., Messaoudi, I., Shen, X., Tomaras, G.D., Shacklett, B.L., Barry, P.A., and Sparger, E.E. (2017), Changes in circulating B cell subsets associated with aging and acute SIV infection in rhesus macaques. PLoS ONE 12(1):e0170154. PMC5240950.

Smith-McCune, K.K., Hilton, J.F., Shanmugasundaram, U., Critchfield, J.W., Greenblatt, R.M., Seidman, D., Averbach, S., Giudice, L.C., and Shacklett, B.L. (2017), Effects of depot-medroxyprogesterone acetate on the immune microenvironment of the human cervix and endometrium: implications for HIV susceptibility. Mucosal Immunology 10(5):1270-78. PMC5496803.

Gosselin, A., Wiche Salinas, T.R., Planas, D., Wacleche, V.S., Zhang, Y., Fromentin, R., Chomont, N., Cohen, E.A., Shacklett, B., Mehraj, V., Ghali, M.P., Routy, J.-P., Ancuta, P. (2017), HIV persists in CCR6+CD4+ T-cells from colon and blood during antiretroviral therapy. AIDS, 31(1):35-48. PMC5131694.

Kiniry, B.E., Ganesh, A., Critchfield, J.W., Hunt, P.W., Hecht, F.M., Somsouk, M., Deeks, S.G., and Shacklett, B.L. (2017), Predominance of weakly cytotoxic, TbetlowEomesNeg CD8+ T-cells in human gastrointestinal mucosa: Implications for HIV infection. Mucosal Immunology 10(4):1008-1020. PMC5423867.

Shanmugasundaram, U., Critchfield, J.W., Pannell, J., Perry, J., Giudice, L.C., Smith-McCune, K., Greenblatt, R.M., and Shacklett, B.L. Phenotype and functionality of CD4+ and CD8+ T-cells in the upper reproductive tract of healthy premenopausal women. Am J of Reproductive Immunology. 2014;71(2):95-108.

Shacklett, B. Mucosal Immunity to HIV, pp 1-13, in:  Encyclopedia of AIDS, 1st Ed., T. Hope, D.D. Richman and M. Stevenson, Eds., New York, Springer Press. 2014; ISBN 978-1-4614-9610-6. DOI: 10.1007/978-1-4614-9610-6_197-1.

Hayes, T.L., Critchfield, J.W., Knight, T.H., McLaughlin, B.E., Yotter, T., McConnell, D.H., Garcia, J.C., Pollard, R.B., Asmuth, D.M., and Shacklett, B.L. (2013), Impact of HAART initiation on CD4+ T-cell repopulation in small and large intestinal mucosa. AIDS 27(6):867-877, PMID: 23262500.

Shaw, J.M., Hunt, P.W., Critchfield, J.W., McConnell, D.H., Garcia, J.C., Pollard, R.B., Somsouk, M., Deeks, S.G., and Shacklett, B.L., (2011), Increased frequency of regulatory T-cells accompanies increased T-cell immune activation in rectal mucosae of HIV+ non-controllers. Journal of Virology 85:11422-11434. PMID: 20880771.

Hatano, H., Hayes, T.L., Dahl, V., Sinclair, E., Lee, T.H., Hoh, R., Lampiris, H., Palmer, S., Hunt, P.W., McCune, J.M., Martin, J.N., Busch, M.P., Shacklett, B.L., and Deeks, S.G. (2011), A randomized, controlled trial of Raltegravir intensification in antiretroviral-treated, HIV-infected patients with suboptimal CD4+ T-cell response. Journal of Infectious Diseases, 203(7):960-8

Review articles and commentaries

Shacklett, B.L., and Anton, P.A. (2010), HIV infection and gut mucosal immune function: Updates on pathogenesis with implications for management and intervention. Current Infectious Disease Reports 12:19-27. PMID: 20174448.

Shacklett, B.L. (2010), Immune responses to HIV and SIV in mucosal tissues: "location, location, location". Current Opinion in HIV and AIDS 5:128-34.

Shacklett, B.L. (2009). Cell-mediated immunity to HIV in the female reproductive tract. Invited review, Journal of Reproductive Immunology, PMID: 19857902.

Shacklett B.L. (2008). Mucosal immunity to HIV: a review of recent literature. Current Opinion in HIV and AIDS, 3:541-547. PMID: 19373019.

Shacklett B.L. (2006). Understanding the lucky few: The conundrum of HIV-exposed, seronegative individuals. Current HIV/AIDS Reports, 3(1):26-31.

Book chapters

Shacklett, B.L., Lemongello, D., and Critchfield, J.W. (2008), Quantifying HIV-1-specific CD8+ T-cell responses using ELISPOT and cytokine flow cytometry, Ch. 24 in: HIV Protocols, 2nd Ed., V.R. Prasad and G.V. Kalpana, Eds., Humana Press, ISBN No. 978-1-58829-859-1. (Listed in PubMed as Methods Mol Biol. 2009;485:359-74. PMID: 19020837.

Shacklett, B.L., Lemongello, D., and Critchfield, J.W. (2008), Isolating mucosal lymphocytes from biopsy tissue for cellular immunology assays, Ch. 23 in: HIV Protocols, 2nd Ed., V.R. Prasad and G.V. Kalpana, Eds., Humana Press, in press, ISBN No. 978-1-58829-859-1. (Listed in PubMed as Methods Mol Biol. 2009;485:347-56. PMID: 19020836

Shacklett B.L. (2007), HIV Infection of the Gastrointestinal Tract, in: Latent Infection by HIV-1 and Related Lentiviruses: New Approaches and Treatment Challenges, A. Brown, Ed., Research Signpost, Trivandrum, pp. 67-82, ISBN No. 978-81-308-0189-6.

Shacklett B.L. and Nixon DF (2006), Methods for detection of antigen-specific T cells by Enzyme-linked immunospot assay (ELISPOT), Ch. 28 in: ASM Manual of Molecular and Clinical Laboratory Immunology, 7th Edition, B. Detrick, R.G. Hamilton and S.D. Douglas, Eds., ASM Press, 1374 pp. , ISBN No. 978-1-55581-364-2.