Protective Immunity againstMycobacterium tuberculosisInduced by Dendritic Cells Pulsed with both CD8⁺- and CD4⁺-T-Cell Epitopes from Antigen 85A

Abstract

Immunization with DNA followed by modified vaccinia virus Ankara strain, both expressing the antigen 85A, induced both CD4+- and CD8+-T-cell responses in BALB/c mice. Following challenge with Mycobacterium tuberculosis, this prime-boost regimen produced protection equivalent to that conferred by Mycobacterium bovis BCG. Following immunization with dendritic cells pulsed with an antigen 85A CD4+- or CD8+-restricted epitope, alone or in combination, copresentation of both epitopes on the same dendritic cell was required for protection, demonstrating that induced CD8+ T cells can play a protective role against tuberculosis

Antigen-Specific CD8+ T Cells and the Development of Central Memory during Mycobacterium tuberculosis Infection

“…In mouse models, CD8 ϩ T cells are critical for optimum immunity, including particular importance in models of latency and immunodeficiency (9,24). Additionally, data exist that CD8 ϩ T cells elicited by vaccination can mediate protection against M. tuberculosis challenge (25)(26)(27). Some debate continues about the absolute requirement for CD8 ϩ T cells in immunity to tuberculosis, in large part because of a greater role for CD4 ϩ T cells compared with CD8 ϩ T cells in some systems (28).…”

Next generation: tuberculosis vaccines that elicit protective CD8+T cells

“…Such findings are taking on even more importance since we now appreciate that antigen-specific CD8 + T cells elicited following infection have cytotoxic activity in vivo [18,19]. Through the use of vaccination studies, Hill's group has shown that an protection correlates with an optimum CD8 + T cell response to Ag85A, which is critically dependant upon CD4 + T cell help [20]. Thus, hosts lacking class II MHC-restricted CD4 + T cells may not be able to mount an optimal CD8 + T cell response to M. tuberculosis, and consequently studies that deplete CD4 + T cells, whether genetically or by treatment with mAb, are likely to overestimate the contribution of CD4 + T cells relative to CD8 + T cells.…”

“…Another way to address the relative importance of CD4 + and CD8 + T cells following DC vaccination is to use synthetic peptides corresponding to well-characterized epitopes from Ag85A recognized by CD4 + or CD8 + T cells. McShane et al used Ag85A peptide-pulsed DC to vaccinate mice and found that DC pulsed with synthetic peptides recognized by both CD4 + and CD8 + T cells induce protective immunity against M. tuberculosis comparable to BCG [20]. In contrast, DC pulsed separately with either the class I or class II MHC-restricted peptide could not induce protection.…”

“…To potentially enhance vaccine efficacy, the gene construct encoding the ESAT6/Ag85B fusion protein was inserted into adenovirus. Interestingly, rAd ESAT6/Ag85B elicits T cells that recognized a significantly different repertoire of epitopes, including a CD8 + T cell dominated response to ESAT6 [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] . In contrast, the frequency of CD4 + T cells recognizing ESAT6 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] and Ag85B 241-255 were markedly reduced.…”

CD8+ T Cells Accumulate in the Lungs of Mycobacterium tuberculosis-Infected Kb−/−Db−/− Mice, But Provide Minimal Protection

“…Adoptive transfer of immune CD8 ϩ T cells (10,11) or immunization with Mtb epitopes recognized by CD8 ϩ T cells can confer partial protection against subsequent challenge with Mtb (12)(13)(14)(15). Furthermore, a recent study using a mouse model of latency and reactivation suggests that CD8 ϩ T cells may be even more important than CD4 ϩ T cells in controlling the latent phase of tuberculosis infection (16).…”