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APCs
Amongst several APCs, DCs are the key APC in humans [10-12] . The human DC arises from a common bone
marrow CD14+ or CD14- myeloid progenitor that also gives rise to the monocyte and is uniquely dependent
on Flt3-ligand for proliferation [13,14] . Antigens presenting cells typically present endogenous or exogenous
antigens on the cell surface in the context of MHC complex class I (for endogenous proteins) or class II (for
[12]
exogenous proteins) molecules . The proteasomes within each cell converts proteins into small peptide
fragments (15-20 amino acids in length) which are then loaded on to MHC complexes and transported to
the cell surface. The peptide fragments are bound within the major clefts of the MHC molecules and are
recognized by the T-lymphocytes (CD8+ T cell for MHC class I and CD4+ T cell for MHC class II) via its
[15]
clonotypically unique TCR .
Cross priming of T-lymphocytes
The mere encounter of a cytotoxic T-cell and a cognate foreign antigen is not enough for antigen recognition
and expansion. Additional signals that arise out of receptor-ligand interaction between the T-lymphocytes
and APCs are necessary for an active immune response to occur and is called cross priming of T-cells.
DCs are called “immature” when they have not encountered antigen yet but have a higher capacity for
[16]
phagocytosis . Immature DCs are not capable of causing T-lymphocyte expansion but can produce
immune tolerance when presenting self-antigens by causing T cell deletion or induction of regulatory
T-lymphocytes [11,16,17] . Maturation of DCs occur in the lymph nodes and within areas of lymphocyte
predominance thus increasing the chances of lymphocyte encounter and cross priming. Productive
encounter of the TCR of CD8+ or CD4+ lymphocytes with p-MHC-I or p-MHC-II complexes respectively
on the mature DCs (first signal) requires the ligation of lymphocyte receptor CD28 of the CD8+ lymphocytes
with its ligand (CD86) on DCs (the second signal or co-stimulation) [18-20] , as CD-28 deficient mice frequently
[21]
have deficient T-cell responses . The interaction of CD40 on CD4+ lymphocytes with the CD40-L on the
[17]
mature DCs is required for proper priming of the CTLs via CD28 and CD86 . Around the same time as
the CD28-CD86 interaction, upregulation of the inhibitory receptor, cytotoxic T-lymphocyte antigen-4
(CTLA4), occurs and engages with CD80 (B7-2) (with a higher affinity compared to CD28) on DCs resulting
[22]
in dampening of the T-cell response to prevent excessive immune reaction to antigen stimulus .

CD8+ lymphocyte subsets and immunologic memory
The CD8+ cytotoxic T-cells are essential for killing viral, protozoal, intracellular bacteria organisms and
[23]
has a key role in preventing tumor growth and eradicating established tumors . It also plays a significant
part in mediating effectiveness of standard cytotoxic therapies for cancer [24,25] . In the context of eliminating
microorganisms and tumor control, its cytocidal effects are mediated via (1) perforin and granzymes
through induction of caspases (identified by the expression of CD107a on degranulating cells); (2) the Fas/
Fas Ligand; (3) cytotoxicity aimed at tumor stromal cells including tumor vasculature; (4) secretion of tumor
necrosis factor-α (TNFα) and interferon-γ (IFN-γ) that in turn induce tumor cell senescence; and (5) an anti-
angiogenic effect by targeting tumor associated macrophages and secretion of IFN-γ (a known inhibitor of
[23]
tumor angiogenesis) . Encounter of naïve CD8+ T cells with p-MHC I complex on DCs results in a series
of events grouped into three phases; (1) a multi-log clonal expansion of CTLs with capabilities of peripheral
tissue homing, release of effector cytokine, and consequent cytotoxicity; (2) a contraction or “death” phase
when there is rapid apoptosis of antigen-specific T-cells; and (3) development of long-lived antigen-specific
cells that represent “memory” cells which reside in the peripheral lymph nodes (central memory cells) or can
home in into the peripheral tissues where infection/tumor exist (effector memory cells) [26,27] . The attributes
of these memory cells encapsulate the hallmarks of immunologic memory; increased precursor frequency
compared to naïve lymphocytes, capacity for antigen-independent renewal in response to cytokines (IL-7,
IL-15, and IL-21), procurement of effector functions and clonal expansion upon re-challenge providing
[26]
long-term protection of the host from future pathogens or tumor recurrences . Immunophenotypes of
[27]
the different CD8+ T cells are listed in Figure 1 . Naïve CD8+ T cells express C-C chemokine receptor
type 7 (CCR7) and CD62L to allow homing to lymphoid tissues [26,27] . Central memory CD8+ lymphocytes
are antigen-experienced cells that express CCR7 and CD62L allowing them to easily extravasate through